JPWO2020075790A1 - STING working compound - Google Patents

Abstract

An object of the present invention is to provide a pharmaceutical product containing a compound having an operative activity against STING as an active ingredient. As a result of diligent studies by the inventors of the present invention, as a substance capable of solving such a problem, the following general formula (I-1) [Chemical formula 1] [All symbols in the formula are detailed. It has the same meaning as that described in the book. ], And the like, and completed the present invention. Since the compounds represented by the general formula (I-1) of the present invention have operative activity against STING, they can be used as active ingredients for suppressing the progression of cancer or infectious diseases, suppressing recurrence, and / or therapeutic agents.

Description

The present invention has the general formula (I).

[In the formula, all symbols have the same meaning as described below. ], Their N-oxides, their prodrugs, their pharmaceutically acceptable salts or their solvates and the general formula (I-1).

[In the formula, all symbols have the same meaning as described below. ], N-oxides thereof, pharmaceutically acceptable salts thereof or solvates thereof (hereinafter, these compounds may be referred to as "compounds of the present invention" in the present specification. ) And pharmaceutical compositions containing any of these as active ingredients and their pharmaceutical uses.

STING (Stimulation of Interferon Genes) is an endoplasmic reticulum-localized four-transmembrane protein and is known to be involved in innate immunity. When foreign double-stranded DNA appears in the cytoplasm due to infection or the like, cyclic GMP-AMP synthase (cGAS) is activated and cyclic GMP-AMP (cGAMP) is synthesized. This cGAMP binds to the endoplasmic reticulum STING and induces the production of type I interferon (IFN). On the other hand, it is known that cyclic dinucleotides such as cyclic Di-GMP, which was first identified as a second messenger of bacteria and later confirmed to exist in mammals, also directly binds to STING and activates it (non-patent documents). 1).

Furthermore, STING is also known to be involved in autoimmune diseases and tumor immunity. For example, it has been shown that abnormal host DNA leaks from the nucleus, activates STING, and induces an pro-inflammatory response, indicating its involvement in autoimmune diseases. The STING pathway also detects tumor-derived DNA and promotes a T cell response to the tumor. The STING-agonizing compound administered to a mouse tumor induces an acquired immune response to cause tumor regression (Non-Patent Document 2), and an activating molecule of the STING pathway enhances IFN production and exhibits an antiviral effect. (Non-Patent Document 3) is known.

So far, as STING working compounds, so-called cyclic dimerized nucleic acids as disclosed in Patent Documents 1 to 3 and compounds of acyclic dimerized nucleic acids as disclosed in Patent Documents 4 to 7 have been used. Although it has been reported, no STING-working compound having a structure similar to that of the compound of the present invention has been reported.

International Publication No. 2017/03933 International Publication No. 2017/186711 International Publication No. 2017/106740 International Publication No. 2017/175156 U.S. Patent Application Publication No. 2017/0050967 U.S. Patent Application Publication No. 2017/0146519 International Publication No. 2018/0674223

Devaux L. et. Al., Curr. Opi. Microbiol. 41, 21-28 (2018) Corrales L. et. Al., Cell Rep. 11 (7), 1018-1030 (2015) Sali T.M. et. Al., PLoS Pathog., 11 (12): e1005324

An object of the present invention is to provide a pharmaceutical product containing a compound having an operative activity against STING as an active ingredient.

As a result of diligent research to find a compound having an agonistic activity on STING, the present inventors have found the following compounds and completed the present invention.

That is, the present invention is as follows.
[1] General formula (I)

[In the formula, X and Y each represent -CH = or a nitrogen atom (where both X and Y do not represent -CH = at the same time), Z represents an oxygen atom or a sulfur atom, and T represents a sulfur atom. , Carbon atom or nitrogen atom, ring A represents a 5-7 member monocycle, ring B represents a 5-7 member monocycle or an 8-10 member bicycle, L ¹ represents a bond, − O -, - CONH -, - CO -, - CO 2 -, - S -, - SO 2 - or an -SO-, ^{L 2} is a bond, C1 -3 alkylene group, C3-7 cycloalkylene group Alternatively, it represents a phenylene group, where R ¹ is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, N (R ^1a ) ₂ (where, the two R ^1a are independent hydrogen atoms or C1 to 4 alkyl groups, respectively. ), C1-4 alkyl group, carboxy group, C1-4 alkoxycarbonyl group, C1-4 haloalkyl group, methyl-d ₃ group, C3-7 cycloalkyl group, phenyl group or 3-7 member monocyclic group Representing a non-aromatic heterocycle, R ² represents a hydrogen atom, a halogen atom, a hydroxyl group, an oxo group, a nitro group, a cyano group, a C1 to 4 alkoxy group or −CH ₂ NR ^2a R ^2b or NR ^2a R ^2b (here). , R ^2a represents a hydrogen atom or a C1-4 alkyl group, R ^2b represents a hydrogen atom), m represents an integer of 0 or 1, and R ³ represents a hydrogen atom, a halogen atom, a hydroxyl group, It represents a C1-4 alkyl group, a C1-4 alkoxy group, a C1-4 haloalkyl group, a C1-4 haloalkoxy group or an amino group, and n represents an integer of 1 to 16 (where n is 2 or more, when n is 2 or more). groups represented by a plurality of ^{R 3} may be the same or different.), ^{R 4} represents a hydrogen atom, C1 -4 alkyl group or a carboxy group, ^{R 5} represents a C1 -4 alkyl group, p is 0 (here, when p is 2 or more, groups represented by a plurality of R ⁵ may be the same or different.) represents an integer of to 5, R ⁶ represents a hydrogen atom or a C1~4 alkyl group, R ⁷ represents a hydrogen atom. Note that b represents the bonding position of the ring B. ], Their N-oxides, their prodrugs, their pharmaceutically acceptable salts or their solvates;
[2] Ring A is a 5- to 6-membered monocyclic ring containing (a) a C5 to 6 monocyclic carbocycle or (b) 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. The compounds according to the previous section [1], their N-oxides, their prodrugs, their pharmaceutically acceptable salts or their solvates, which are heterocycles;
[3] Ring B is a 5- to 6-membered monocyclic ring containing (a) a C5 to 6 monocyclic carbocycle or (b) 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. The compounds according to the above paragraph [1] or [2], their N-oxides, their prodrugs, their pharmaceutically acceptable salts or their solvates, which are heterocycles;
[4] Ring A is a 5- to 6-membered monocyclic aromatic heterocycle containing (a) a benzene ring or (b) 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. , The compounds according to the preceding paragraph [1] or [3], their N-oxides, their prodrugs, their pharmaceutically acceptable salts or their solvates;
[5] Ring B is a 5- to 6-membered monocyclic aromatic heterocycle containing (a) a benzene ring or (b) 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. , The compound according to any one of the preceding paragraphs [1], [2] and [4], its N-oxide compound, their prodrugs, their pharmaceutically acceptable salts or their solvates;
[6] Ring A is a 5- to 6-membered monocyclic aromatic nitrogen-containing heterocycle containing 1 to 4 nitrogen atoms and no other heteroatoms, as described in the preceding paragraphs [1], [3] and [6]. 5] The compound according to any one of the above, its N-oxide form, their prodrugs, their pharmaceutically acceptable salts or their solvates;
[7] The compound according to any one of the above items [1] to [6], wherein Z is an oxygen atom, an N-oxide compound thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. Solvation;
[8] The compound according to any one of the above items [1] to [7], wherein X is a nitrogen atom and Y is −CH =, its N-oxide compound, their prodrugs, and their pharmaceuticals. Tolerable salts or solvates thereof;
[9] Of the general formula (I)

[In the formula, the arrow is bonded to the carbon atom represented by b in the general formula (I), and the other symbols have the same meanings as described above. ] Is the following formula (Ib)

[In the formula, U represents a nitrogen atom or a carbon atom (where m represents 0 when U represents a nitrogen atom and m represents 1 when U represents a carbon atom), W represents − CR ³ = or represents a nitrogen atom, V represents -CH = or a nitrogen atom, and if formula (Ib) has more than one R ³ , the groups they represent may be the same or different, with other symbols It has the same meaning as above. ], Which is the group according to any one of the preceding paragraphs [1] to [8], its N-oxides, their prodrugs, their pharmaceutically acceptable salts or their solvates. Stuff;
[10] The compound represented by the general formula (I) is the general formula (II).

[In the formula, all symbols have the same meaning as above. ], The compounds according to the preceding paragraph [1], their N-oxides, their prodrugs, their pharmaceutically acceptable salts or their solvates;
[11] The compound according to any one of the above items [1] to [10], wherein T is a nitrogen atom, an N-oxide compound thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. Solvation;
[12] The compound according to any one of the above items [9] to [11], wherein U is a carbon atom, an N-oxide compound thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. Solvation;
[13] Ring A is pyrazole, triazole (eg, 1,2,3-triazole and 1,2,4-triazole), tetrazole, oxazole, isoxazole, imidazole, thiazole or isothiazole, the preceding paragraph [1]. , [3], [5] and any one of [7] to [12], their N-oxides, their prodrugs, their pharmaceutically acceptable salts or their solvates. Stuff;
[14] The compound represented by the general formula (I) is the general formula (III).

[In the formula, pa represents an integer of 0 to 2, and other symbols have the same meanings as described above. ], The compounds according to the preceding paragraph [1], their N-oxides, their prodrugs, their pharmaceutically acceptable salts or their solvates;
[15] L ² of the general formula (I), the general formula (II), and the general formula (III) (hereinafter, may be abbreviated as "general formula (I), etc.") The compound according to any one of the above items [1] to [14], which is an alkylene group, an N-oxide compound thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof;
[16] ^{L 1} such as the general formula (I), -O -, - CONH -, - CO -, - CO 2 -, - S -, - SO 2 - or -SO-, items [1] The compound according to any one of [15], its N-oxide form, their prodrug, their pharmaceutically acceptable salt or their solvate;
[17] L ^{1 of the} general formula (I) or the like is -CONH- (where the left side of the group is bonded to ring B), -CO-, -CO _2- , -S-, -SO _2- Or -SO-, the compound according to any one of the preceding paragraphs [1] to [15], its N-oxides, their prodrugs, their pharmaceutically acceptable salts or their solvates. ;
[18] The compound according to any one of the above items [1] to [17], wherein R ¹ is a hydrogen atom, a hydroxyl group, a C1 to 4 alkyl group or a carboxy group, an N-oxide compound thereof, and a prodrug thereof. , Their pharmaceutically acceptable salts or their solvates;
[19] The compound according to any one of the above items [1] to [17], wherein R ¹ is a hydrogen atom or a C1 to 4 alkyl group, its N-oxide compound, their prodrugs, and their pharmaceuticals. Acceptable salts or solvates thereof;
[20] The compound according to any one of the above items [1] to [19], wherein R ² is a nitro group or NR ^2a R ^2b , its N-oxide compound, their prodrugs, and their pharmaceutically Acceptable salts or solvates thereof;
[21] The compound according to any one of the above items [1] to [20], the N-oxide compound thereof, their prodrugs, and their pharmaceutically acceptable compounds, wherein both R ^2a and R ^2b are hydrogen atoms. Salts or solvates thereof;
[22] The compound according to any one of the above items [1] to [21], wherein R ³ is a hydrogen atom, a halogen atom or a hydroxyl group, its N-oxide compound, their prodrugs, and their pharmaceutically Acceptable salts or solvates thereof;
[23] R ⁴ is a hydrogen atom, items [1] to compound according to one of [22], its N- oxide thereof, a prodrug thereof, salts their pharmaceutically acceptable or Those solvates;
[24] R ⁶ is a hydrogen atom, items [1] to compound according to one of [23], its N- oxide thereof, a prodrug thereof, salts their pharmaceutically acceptable or Those solvates;
[25] The compound according to any one of the above items [1] to [24], wherein p and pa are zero or one, their N-oxides, their prodrugs, and their pharmaceutically acceptable substances. Salts or solvates thereof;
[26] The compound represented by the general formula (I) is
(1) 4- (4-Amino-2-fluoro-5-methoxyphenyl) -7- (1H-pyrazole-4-yl) isoxazolo [5,4-c] pyridine-3-amine,
(2) 4- (4-Amino-2-fluoro-5-methoxyphenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridine-3-amine,
(3) 4- (4-Amino-3-methoxyphenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridine-3-amine,
(4) 4- (4-Amino-2-fluoro-5- (methylthio) phenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine,
(5) 4- (4-Amino-2-fluoro-5- (methoxy-d ₃ ) phenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine,
(6) 4- (4-Amino-2-fluoro-5- (methylsulfonyl) phenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine,
(7) 4- (4-Amino-5- (ethylthio) -2-fluorophenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine,
(8) 4- (4-Amino-2-fluoro-5- (methylsulfinyl) phenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine,
(9) 4- (4-Amino-2-fluoro-3-methoxyphenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridine-3-amine,
(10) Methyl 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorobenzoate,
(11) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorobenzoic acid,
(12) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorobenzamide,
(13) 4- (4-Amino-2-fluoro-5-methoxyphenyl) -7- (3-methyl-1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine,
(14) 1- (2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorophenyl) ethane- 1-on,
(15) 4- (4-Amino-2-chloro-5- (methylthio) phenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine,
(16) Ethyl 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorobenzoate,
(17) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluoro-N-methylbenzamide,
(18) 1- (2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorophenyl) propane- 1-on,
(19) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -N-ethyl-4-fluorobenzamide,
(20) 1- (2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) phenyl) ethane-1-one,
(21) Methyl 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) benzoate,
(22) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -N-propylbenzamide,
(23) 1- (2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorophenyl) butane- 1-on,
(24) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluoro-N-propylbenzamide,
(25) 1- (2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) phenyl) butane-1-one,
(26) 2-Hydroxyethyl 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorobenzoate,
(27) 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) benzamide,
(28) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -N-methylbenzamide,
(29) 1- (2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-hydroxyphenyl) ethane- 1-on,
(30) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -N-ethylbenzamide,
(31) 1- (2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) phenyl) propan-1-one,
(32) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-chloro-N-ethylbenzamide,
(33) 4- (2-Fluoro-5-methoxy-4-nitrophenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine,
(34) 1- (2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isothiazolo [4,5-c] pyridin-4-yl) -4-fluorophenyl) ethane- 1-one and (35) 4- (4-amino-2-fluoro-5- (trifluoromethyl) phenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridine- The compound according to the previous item [1], its N-oxide compound, their prodrugs, their pharmaceutically acceptable salts or their solvates, which are compounds selected from the group consisting of 3-amines;

[1-1] General formula (I-1)

[In the formula, R ^2c is a hydrogen atom, a hydroxyl group, a halogen atom, an oxo group, a nitro group, a cyano group, a C1 to 4 alkoxy group or −CH ₂ NR ^2d R ^2e or NR ^2d R ^2e (where R ^2d is , Hydrogen atom, C1-4 alkyl group or R ^FR , R ^2e represents hydrogen atom), R ^4a represents hydrogen atom, C1-4 alkyl group, carboxy group or R ^FR , R ^6a Represents a hydrogen atom, C1-4 alkyl group or R ^FR , where R ^FR is
(I)-(CR ^Fb ₂ ) _q OP (= O) (OR ^Fa ) ₂ [In the formula, R ^Fa is a hydrogen atom, a C1-4 alkyl group, a C3-6 cycloalkyl group, − (CH ₂ ) ₂ OH or −CH ₂ OCO ₂ CH (CH ₃ ) ₂ represents, ^RFb represents a hydrogen atom or a methyl group, and q represents an integer of 1 or 2 (here, a plurality of ^RFbs). The groups represented by may be the same or different.) (Hereinafter, the ^-. _{(CR Fb} 2) are collectively ^{q OP (= O) (OR} Fa) 2 group may be abbreviated as "phosphonooxyalkyl group"), or (ii) in vivo As a result of decomposition, it represents a compound represented by the general formula (I), its N-oxide form, a pharmaceutically acceptable salt thereof or a free radical that produces a solvate thereof, and other symbols are as described above. Represents the same meaning. However, two or more of R ^2d , R ^4a and R ^6a do not represent R ^FR at the same time. ], Its N-oxides, their pharmaceutically acceptable salts or their solvates;
[1-2] Ring A is a 5-6 membered compound containing (a) a C5-6 monocyclic carbocycle or (b) 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. The compound according to the previous section [1-1], its N-oxide compound, a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a cyclic heterocycle;
[1-3] Ring B is a 5-6 membered compound containing (a) a C5-6 monocyclic carbocycle or (b) 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. The compound according to the above item [1-1] or [1-2], an N-oxide compound thereof, a pharmaceutically acceptable salt thereof or a solvent product thereof, which is a cyclic heterocycle;
[1-4] Ring A is a 5- to 6-membered monocyclic aromatic heterocycle containing (a) a benzene ring or (b) 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. The compounds according to the preceding paragraph [1-1] or [1-3], their N-oxides, their pharmaceutically acceptable salts or their solvates;
[1-5] Ring B is a 5- to 6-membered monocyclic aromatic heterocycle containing (a) a benzene ring or (b) 1 to 4 heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom. The compound according to any one of the above items [1-1], [1-2] and [1-4], its N-oxide compound, a pharmaceutically acceptable salt thereof or a solvate thereof. Stuff;
[1-6] Ring A represents a 5- to 6-membered monocyclic aromatic nitrogen-containing heterocycle containing 1 to 4 nitrogen atoms and no other heteroatoms. 1-3] and any one of [1-5], their N-oxides, their pharmaceutically acceptable salts or their solvates;
[1-7] The compound according to any one of the above items [1-1] to [1-6], wherein Z is an oxygen atom, an N-oxide compound thereof, a pharmaceutically acceptable salt thereof, or them. Solvation;
[1-8] The compound according to any one of the above items [1-1] to [1-7], wherein X is a nitrogen atom and Y is −CH =, its N-oxide compound, and their pharmacy. Tolerable salts or solvates thereof;
[1-9] Of the general formula (I-1)

[In the formula, the arrow is bonded to the carbon atom represented by b in the general formula (I-1), and the other symbols have the same meanings as described above. ] Is the formula (Ib-1)

[In the formula, all symbols have the same meaning as above. ], The compound according to any one of the above items [1-1] to [1-8], its N-oxide compound, a pharmaceutically acceptable salt thereof, or a solvate thereof. ;
[1-10] The compound represented by the general formula (I-1) is the general formula (II-1).

[In the formula, all symbols have the same meaning as above. ], The compound according to the preceding paragraph [1-1], its N-oxide form, a pharmaceutically acceptable salt thereof or a solvate thereof;
[1-11] The compound according to any one of the above items [1-1] to [1-10], wherein T is a nitrogen atom, an N-oxide compound thereof, a pharmaceutically acceptable salt thereof or them. Solvation;
[1-12] The compound according to any one of the above items [1-9] to [1-11], wherein U is a carbon atom, an N-oxide compound thereof, a pharmaceutically acceptable salt thereof, or them. Solvation;
[1-13] Ring A is pyrazole, triazole (eg, 1,2,3-triazole and 1,2,4-triazole), tetrazole, oxazole, isoxazole, imidazole, thiazole or isothiazole. 1-1], [1-3], [1-5] and [1-7] to [1-12], the compound according to any one of the above, its N-oxide form, and pharmaceutically acceptable thereof. Salts or their solvates;
[1-14] The compound represented by the general formula (I-1) is the general formula (III-1).

[In the formula, all symbols have the same meaning as above. ], The compound according to the preceding paragraph [1-1], its N-oxide form, a pharmaceutically acceptable salt thereof or a solvate thereof;
[1-15] Of the general formula (I-1), the general formula (II-1) and the general formula (III-1) (hereinafter, may be abbreviated as "general formula (I-1) or the like"). The compound according to any one of the above items [1-1] to [1-14], the N-oxide compound thereof, and a pharmaceutically acceptable salt thereof, wherein L ² is a bond or a C1 to 3 alkylene group. Or their solvates;
[1-16] Formula (I-1) is ^{L 1,} such as, -O -, - CONH -, - CO -, - CO 2 -, - S -, - is or -SO-, - SO ₂ The compound according to any one of the above items [1-1] to [1-15], its N-oxide form, a pharmaceutically acceptable salt thereof or a solvate thereof;
[1-17] L ^{1 of the} general formula (I-1) or the like is -CONH- (where the left side of the group is bonded to ring B), -CO-, -CO _2- , -S-, The compound according to any one of the above items [1-1] to [1-15], which is -SO _2- or -SO-, its N-oxide form, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof. Solvation;
[1-18] The compound according to any one of the above items [1-1] to [1-17], wherein R ¹ is a hydrogen atom, a hydroxyl group, a C1-4 alkyl group or a carboxy group, and N-oxide thereof. The body, their pharmaceutically acceptable salts or their solvates;
[1-19] The compound according to any one of the above items [1-1] to [1-17], wherein R ¹ is a hydrogen atom or a C1 to 4 alkyl group, an N-oxide compound thereof, and their pharmacy. Tolerable salts or solvates thereof;
[1-20] The compound according to any one of the above items [1-1] to [1-19], wherein R ^2c is a nitro group or NR ^2d R ^2e , its N-oxide form, and their pharmaceutical use. Tolerable salts or solvates thereof;
[1-21] The compound according to any one of the above items [1-1] to [1-20], wherein R ³ is a hydrogen atom, a halogen atom or a hydroxyl group, its N-oxide compound, and their pharmaceuticals. Tolerable salts or solvates thereof;
[1-22] The compound according to any one of the above items [1-1] to [1-21], wherein R ^2d is a hydrogen atom or R ^FR , an N-oxide compound thereof, and pharmaceutically acceptable thereof. Salts or solvates thereof;
[1-23] The compound according to any one of the above items [1-1] to [1-22], wherein both R ^4a and R ^6a are hydrogen atoms, their N-oxides, and their pharmaceutically acceptable substances. Salts or solvates thereof;
[1-24] The compound according to any one of the above items [1-1] to [1-21], wherein R ^4a is a hydrogen atom or R ^FR , an N-oxide compound thereof, and pharmaceutically acceptable thereof. Salts or solvates thereof;
[1-25] The compound according to any one of the above items [1-1] to [1-21] and [1-24], wherein both R ^2d and R ^6a are hydrogen atoms, and an N-oxide compound thereof. Their pharmaceutically acceptable salts or their solvates;
[1-26] The compound according to any one of the above items [1-1] to [1-21], wherein R ^6a is a hydrogen atom or R ^FR , an N-oxide compound thereof, and pharmaceutically acceptable thereof. Salts or solvates thereof;
[1-27] The compound according to any one of the above items [1-1] to [1-21] and [1-26], wherein both R ^2d and R ^4a are hydrogen atoms, and an N-oxide compound thereof. Their pharmaceutically acceptable salts or their solvates;
[1-28] R ^FR is − (CR ^Fb ₂ ) _q OP (= O) (OR ^Fa ) ₂ [In the formula, all symbols have the same meanings as described above. ], The compound according to any one of the preceding paragraphs [1-1] to [1-27], its N-oxides, pharmaceutically acceptable salts thereof or solvates thereof;
[1-29] − (CR ^Fb ₂ ) _q OP (= O) (OR ^Fa ) ₂ represented by R ^FR is −CH ₂ OP (= O) (OH) ₂ , −CH (CH ₃ ) OP (= O) (OH) ₂ or −CH ₂ OP (= O) (OH) (OCH ₂ OCO ₂ CH (CH ₃ ) ₂ ) The compound according to the previous section [1-28], its N-oxide compound, and their N-oxides. Pharmaceutically acceptable salts or solvates thereof;
[1-30] The R ^FR is − (CR ^Fb ₂ ) _q OP (= O) (OR ^Fa ) ₂ , and the pharmaceutical drug according to any one of the above items [1-1] to [1-28]. Acceptable salts are alkali metal salts (eg lithium salt, sodium salt or potassium salt), alkaline earth metal salts (eg calcium salt), magnesium salts, zinc salts, ammonium salts or A pharmaceutically acceptable salt of the compound according to any one of the above items [1-1] to [1-28], which is an organic amine salt, or a solvate thereof;
[1-31] The organic amine salt is an aliphatic amine salt (for example, methylamine salt, dimethylamine salt, cyclopentylamine salt, trimethylamine salt, triethylamine salt, dicyclohexylamine salt, monoethanolamine salt, diethanolamine salt, triethanolamine). Salts, procaine salts, meglumin salts, diethanolamine salts, tris (hydroxymethyl) aminomethane salts or ethylenediamine salts, etc.), aralkylamine salts (eg, benzylamine salts, phenethylamine salts, N, N-dibenzylethylenediamine salts or venetamine salts, etc.) ), Heterocyclic aromatic amine salts (eg, piperidine salts, pyridine salts, picolin salts, quinoline salts or isoquinolin salts, etc.), quaternary ammonium salts (eg, tetramethylammonium salts, tetraethylamonium salts, benzyltrimethylammonium salts, etc.) , Benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt or tetrabutylammonium salt, etc.), basic amino acid salt (eg, arginine salt or lysine salt, etc.) or N-methyl-D-glucamine salt. A pharmaceutically acceptable salt of the compound according to the preceding paragraph [1-30] or a solvate thereof;
[1-32] The compound according to any one of the above items [1-1] to [1-31], wherein p and pa are zero or 1, the N-oxide compound thereof, and pharmaceutically acceptable thereof. Salts or solvates thereof;
[1-33] The compound represented by the general formula (I-1) is
(1) 4- (4-Amino-2-fluoro-5-methoxyphenyl) -7- (1H-pyrazole-4-yl) isoxazolo [5,4-c] pyridine-3-amine,
(2) 4- (4-Amino-2-fluoro-5-methoxyphenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridine-3-amine,
(3) 4- (4-Amino-3-methoxyphenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridine-3-amine,
(4) 4- (4-Amino-2-fluoro-5- (methylthio) phenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine,
(5) 4- (4-Amino-2-fluoro-5- (methoxy-d ₃ ) phenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine,
(6) 4- (4-Amino-2-fluoro-5- (methylsulfonyl) phenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine,
(7) 4- (4-Amino-5- (ethylthio) -2-fluorophenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine,
(8) 4- (4-Amino-2-fluoro-5- (methylsulfinyl) phenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine,
(9) 4- (4-Amino-2-fluoro-3-methoxyphenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridine-3-amine,
(10) Methyl 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorobenzoate,
(11) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorobenzoic acid,
(12) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorobenzamide,
(13) 4- (4-Amino-2-fluoro-5-methoxyphenyl) -7- (3-methyl-1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine,
(14) Methyl 2-amino-5- (3-amino-7- (1-((phosphonooxy) methyl) -1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl)- 4-Fluorobenzoate,
(15) 1- (2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorophenyl) ethane- 1-on,
(16) 4- (4-Amino-2-chloro-5- (methylthio) phenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine,
(17) Ethyl 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorobenzoate,
(18) (4- (4- (5-Acetyl-4-amino-2-fluorophenyl) -3-aminoisoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazole-1- Il) Methyl dihydrogen phosphate,
(19) Ethyl 2-amino-5- (3-amino-7- (1-((phosphonooxy) methyl) -1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl)- 4-Fluorobenzoate,
(20) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluoro-N-methylbenzamide,
(21) 1- (2-Amino-5- (3-Amino-7- (1H-Pyrazole-4-yl) isoxazolo [4,5-c] Pyridine-4-yl) -4-fluorophenyl) Propane- 1-on,
(22) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -N-ethyl-4-fluorobenzamide,
(23) 1- (2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) phenyl) ethane-1-one,
(24) Methyl 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) benzoate,
(25) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -N-propylbenzamide,
(26) 1- (2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorophenyl) butane- 1-on,
(27) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluoro-N-propylbenzamide,
(28) 1- (2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) phenyl) butane-1-one,
(29) 2-Hydroxyethyl 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorobenzoate,
(30) 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) benzamide,
(31) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -N-methylbenzamide,
(32) (4- (3-Amino-4- (4-amino-5- (ethylcarbamoyl) -2-fluorophenyl) isoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazole-1 -Il) Methyl dihydrogen phosphate,
(33) 1- (2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-hydroxyphenyl) ethane- 1-on,
(34) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -N-ethylbenzamide,
(35) 1- (2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) phenyl) propan-1-one,
(36) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-chloro-N-ethylbenzamide,
(37) (4- (3-Amino-4- (4-amino-2-fluoro-5- (methylthio) phenyl) isoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazole-1- Il) Methyl dihydrogen phosphate,
(38) (4- (3-Amino-4- (4-amino-2-fluoro-5-propionylphenyl) isoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazol-1-yl) Methyl dihydrogen phosphate,
(39) (4- (4- (3-Acetyl-4-aminophenyl) -3-aminoisoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazole-1-yl) methyldi Hydrogen phosphate,
(40) 4- (2-Fluoro-5-methoxy-4-nitrophenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine,
(41) (4- (3-Amino-4- (4-amino-2-fluoro-5- (methylsulfonyl) phenyl) isoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazole-1 -Il) Methyl dihydrogen phosphate,
(42) (4- (3-Amino-4- (4-amino-5- (ethylcarbamoyl) -2-chlorophenyl) isoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazole-1- Il) Methyl dihydrogen phosphate,
(43) 1- (2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isothiazolo [4,5-c] pyridin-4-yl) -4-fluorophenyl) ethane- 1-one and (44) 4- (4-amino-2-fluoro-5- (trifluoromethyl) phenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridine- The compound according to the previous section [1-1], its N-oxide compound, a pharmaceutically acceptable salt thereof or a solvent product thereof, which is a compound selected from the group consisting of 3-amines;
[1-34] The compound represented by the general formula (I-1) is
(1) Methyl 2-amino-5- (3-amino-7- (1-((phosphonooxy) methyl) -1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl)- 4-Fluorobenzoate,
(2) (4- (4- (5-Acetyl-4-amino-2-fluorophenyl) -3-aminoisoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazole-1- Il) Methyl dihydrogen phosphate,
(3) Ethyl 2-amino-5- (3-amino-7- (1-((phosphonooxy) methyl) -1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl)- 4-Fluorobenzoate,
(4) (4- (3-Amino-4- (4-amino-5- (ethylcarbamoyl) -2-fluorophenyl) isoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazole-1 -Il) Methyl dihydrogen phosphate,
(5) (4- (3-Amino-4- (4-amino-2-fluoro-5- (methylthio) phenyl) isoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazole-1- Il) Methyl dihydrogen phosphate,
(6) (4- (3-Amino-4- (4-amino-2-fluoro-5-propionylphenyl) isoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazol-1-yl) Methyl dihydrogen phosphate,
(7) (4- (4- (3-Acetyl-4-aminophenyl) -3-aminoisoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazole-1-yl) methyldi Hydrogen phosphate,
(8) (4- (3-Amino-4- (4-amino-2-fluoro-5- (methylsulfonyl) phenyl) isoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazol-1 -Il) Methyl dihydrogen phosphate, and (9) (4- (3-amino-4- (4-amino-5- (ethylcarbamoyl) -2-chlorophenyl) isoxazolo [4,5-c] pyridine-7- Il) -1H-pyrazole-1-yl) A compound selected from the group consisting of methyl dihydrogen phosphate, the compound according to the preceding paragraph [1-1], its N-oxide form, and pharmaceutically acceptable thereof. Salts or their solvates;
[1-35] The pharmaceutically acceptable salt of the compound according to any one of the above items [1-1] to [1-34] is an alkali metal salt (for example, a lithium salt, a sodium salt or a potassium salt). A pharmaceutically acceptable salt of the compound according to any one of the above items [1-1] to [1-34] or a solvate thereof;
[1-36] The solvate of the compound according to any one of the above items [1-1] to [1-35] or an acceptable salt thereof is a hydrate, the above items [1-1] to [ A solvate of the compound according to any one of 1-35] or a pharmaceutically acceptable salt thereof;

[2-1] Compounds represented by the general formula (I), the general formula (II) or the general formula (III), their N-oxides, their prodrugs, their pharmaceutically acceptable salts or theirs. Pharmaceutical compositions containing solvates and pharmaceutically acceptable carriers;
[2-2] Compounds represented by the general formula (I-1), the general formula (II-1) or the general formula (III-1), their N-oxides, their pharmaceutically acceptable salts or them. A pharmaceutical composition containing a solvate of the above and a pharmaceutically acceptable carrier;
[2-3] The pharmaceutical composition according to the preceding paragraph [2-1] or [2-2], further containing the active ingredient of one or more other anticancer agents;

[3-1] Compounds represented by the general formula (I), the general formula (II) or the general formula (III), their N-oxides, their prodrugs, their pharmaceutically acceptable salts or theirs. Suppressing the progression of cancer or infectious diseases, suppressing recurrence and / or therapeutic agents containing solvates as active ingredients;
[3-2] Compounds represented by the general formula (I-1), the general formula (II-1) or the general formula (III-1), their N-oxides, their pharmaceutically acceptable salts or them. Suppressing the progression of cancer or infectious diseases, suppressing recurrence and / or therapeutic agents containing the solvate of
[3-3] The agent according to the preceding paragraph [3-1] or [3-2], wherein the cancer is solid cancer or blood cancer;
[3-4] Solid cancers include malignant melanoma (eg, malignant melanoma in the skin, oral mucosal epithelium or intraocular cavity), non-small cell lung cancer (eg, flat non-small cell lung cancer and non-flat non-small cell lung cancer). ), Small cell lung cancer, head and neck cancer (eg, oral cancer, nasopharyngeal cancer, mesopharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, salivary adenocarcinoma and tongue cancer), renal cell carcinoma (eg, clear cell renal cell carcinoma) ), Breast cancer, ovarian cancer (eg, serous ovarian cancer and clear cell adenocarcinoma of the ovary), nasopharyngeal cancer, uterine cancer (eg, cervical cancer and uterine body cancer), anal cancer (eg, anal duct cancer), colon Cancer (eg, high frequency microsatellite instability (hereinafter abbreviated as "MSI-H") and / or mismatch repair defect (hereinafter abbreviated as "dMMR") positive colon cancer), rectal cancer, colon cancer , Hepatocyte cancer, esophageal cancer, gastric cancer, esophagogastric junction cancer, pancreatic cancer, urinary epithelial cancer (eg bladder cancer, upper urinary tract cancer, urinary tract cancer, renal pelvis cancer and urinary tract cancer), prostate cancer, oviduct cancer , Primary peritoneal cancer, malignant pleural mesoderma, biliary sac cancer, biliary tract cancer, biliary tract cancer, skin cancer (eg, grape membrane malignant melanoma and Merkel cell carcinoma), testis cancer (embryonic cell tumor), vaginal cancer, genital area Cancer, penis cancer, small bowel cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, spinal tumor, neuroblastoma, myeloma, ocular retinoblastoma, neuroendocrine tumor, brain tumor (eg, glioma) The agent according to the preceding paragraph [3-3], which is one or more cancers selected from tumors (eg, glioma and glioma) and medullary carcinoma) and squamous cell carcinoma;
[3-5] Solid cancer is bone / soft tissue sarcoma (eg, Ewing's sarcoma, pediatric rhabdomyosarcoma, uterine leiomyosarcoma, chondrosarcoma, lung sarcoma, osteosarcoma and congenital fibrosarcoma) or caposarcoma. The agent according to the preceding paragraph [3-3];
[3-6] Hematological cancers include multiple myeloma, malignant lymphoma (eg, non-hodgkin lymphoma (eg, follicular lymphoma, precursor B-cell lymphoblastic lymphoma, chronic B lymphocytic leukemia, nodal marginal zone)) B-cell lymphoma, diffuse large-cell B-cell lymphoma, MALT lymphoma, primary splenic marginal zone B-cell lymphoma, hairy cell leukemia, primary mediastinal large-cell B-cell lymphoma, barkit lymphoma, mantle cell Lymphoma, mycobacterial sarcoma, Cesarie syndrome, chronic or acute lymphocytic leukemia, precursor T-cell lymphoblastic lymphoma, chronic T-lymphoma, large-granular T-cell leukemia, large-granule NK-cell leukemia, peripheral T-cell lymphoma, extranodal NK / T-cell lymphoma, adult T-cell leukemia, vascular central lymphoma, intestinal T-cell lymphoma, Hodgkin-like / Hodgkin-related undifferentiated large-cell lymphoma, B-cell lymphoblastic leukemia, T-cell Lymphomacytic leukemia and lymphoplasmacytic lymphoma) and Hodgkin lymphoma (eg, classical Hodgkin lymphoma and nodular lymphocyte-dominant Hodgkin lymphoma), leukemia (eg, acute myeloid leukemia and chronic myeloid leukemia), central The agent according to the preceding paragraph [3-3], which is one or more cancers selected from primary malignant lymphoma of the nervous system, myelodysplasia syndrome and myeloid proliferation syndrome;
[3-7] The agent according to the preceding paragraph [3-1] or [3-2], wherein the cancer is childhood cancer or cancer of unknown primary origin;
[3-8] The agent according to any one of the preceding paragraphs [3-1] to [3-7], wherein the cancer is a cancer in which the therapeutic effect of another anticancer agent is insufficient or insufficient;
[3-9] The agent according to any one of the preceding items [3-1] to [3-8], wherein the cancer is exacerbated after treatment with another anticancer agent;
[3-10] The agent according to any one of the above items [3-1] to [3-7], wherein the cancer patient is a patient who has not been treated with another anticancer agent;
[3-11] The agent according to any one of the preceding items [3-1] to [3-10], which is prescribed in postoperative adjuvant therapy or neoadjuvant therapy;
[3-12] The preceding paragraph [3-1] to [3-11], wherein the cancer is curative or unresectable, metastatic, recurrent, refractory and / or distant metastatic. Agent;
[3-13] Percentage of tumor cells expressing PD-L1 among tumor cells in tumor tissue (hereinafter abbreviated as "TPS") or number of PD-L1 positive cells (tumor cells, lymphocytes and (Macrophages) is divided by the total number of tumor cells and multiplied by 100 (hereinafter abbreviated as "CPS") is 50% or more, 25% or more, 10% or more, 5% or more or 1% or more. , The agent according to any one of the preceding items [3-1] to [3-12];
[3-14] The agent according to any one of the above items [3-1] to [3-12], wherein the TPS is less than 50%, less than 25%, less than 10%, less than 5% or less than 1%. ;
[3-15] The agent according to any one of the preceding items [3-1] to [3-14], wherein the cancer has MSI-H and / or dMMR;
[3-16] The cancer does not have MSI-H and / or dMMR, or has low-frequency microsatellite instability (hereinafter abbreviated as "MSI-L"), the above paragraph [3-1] to The agent according to any one of [3-14];
[3-17] The agent according to any one of the preceding items [3-4] to [3-16], wherein the malignant melanoma or non-small cell lung cancer is BRAF V600E mutation positive;
[3-18] The agent according to any one of the above items [3-4] to [3-16], wherein the malignant melanoma or non-small cell lung cancer is a BRAF V600 wild type;
[3-19] The agent according to any one of the preceding paragraphs [3-4] to [3-18], wherein the non-small cell lung cancer is EGFR gene mutation positive and / or ALK fusion gene positive;
[3-20] The agent according to any one of the preceding paragraphs [3-4] to [3-18], wherein the non-small cell lung cancer is EGFR gene mutation negative and / or ALK fusion gene negative;
[3-21] Tumor mutation load cancer (hereinafter, abbreviated as "TMB".) Is high frequency (10 ⁶ or more 10 mutations per base), items [3-1] - [3 -20] The agent according to any one item;
[3-22] TMB cancer is low frequency (10 ⁶ mutations per base is less than 10), items [3-1] - agent according to one of [3-20];
[3-23] The agent according to any one of the preceding items [3-1] to [3-22], which is further administered in combination with one or more other anticancer agents;
[4-1] The agent according to the preceding paragraph [3-1] or [3-2], wherein the infectious disease is a symptom caused by a viral infection, a parasitic infection, a bacterial infection or a fungal infection;
[4-2] Virus infections include adenovirus, arenavirus, bunyavirus, calicivirus, coronavirus, phyllovirus, hepadonavirus, herpesvirus, orthomixovirus, papovavirus, paramixovirus, parvovirus, picornavirus. , Poxvirus, Leovirus, Retrovirus, Rabdovirus, Togavirus, Papillomavirus (eg, Human Papillomavirus (HPV)), Human Immunodeficiency Virus (HIV), Poliovirus, Hepatitis Virus (eg, Hepatitis A) Virus (HAV), Hepatitis B virus (HBV), Hepatitis C virus (HCV), Hepatitis D virus (HDV) and Hepatitis E virus (HEV)), Spontaneous pox virus (eg, large and small sputum) , Waxinia virus, influenza virus, rhinovirus, dengue fever virus, horse encephalitis virus, eczema virus, yellow fever virus, no walk virus, human T cell leukemia virus (HTLV-I), hairy cell leukemia virus (HTLV-II), California Encephalitis virus, hunter virus (hemorrhagic fever), mad dog disease virus, Ebola fever virus, Marburg virus, measles virus, epidemic parotitis virus, respiratory rash virus (RSV), simple herpes type 1 (oral herpes), simple Herpes type 2 (pudendal herpes), herpes zoster (varicella / herpes zoster virus), cytomegalovirus (CMV), Epstein-bar virus (EBV), flavivirus, foot-and-mouth epidemic virus, chikungunyavirus, lassavirus, arenavirus or carcinogenic The agent according to the preceding paragraph [4-1], which is an infectious disease caused by a virus;

[5-1] An effective dose of the compound represented by the general formula (I), its N-oxide form, their prodrug, their pharmaceutically acceptable salt or their solvate is administered. Methods of controlling the progression, recurrence and / or treatment of cancer or infection, consisting of administration to patients in need;
[5-2] Patients who need to administer an effective dose of the compound represented by the general formula (I-1), its N-oxide form, their pharmaceutically acceptable salt or their solvate. A method of suppressing the progression of cancer or an infectious disease, suppressing recurrence, and / or treating the disease;

[6-1] Compounds represented by the general formula (I), their N-oxides, their prodrugs, and their pharmaceuticals for use in suppressing the progression, suppressing recurrence and / or treating cancer or infectious diseases. Tolerable salts or solvates thereof;
[6-2] Compounds represented by the general formula (I-1), N-oxides thereof, and pharmaceutically acceptable compounds thereof for use in suppressing the progression, suppressing recurrence and / or treating cancer or infectious diseases. Salts or solvates thereof;

[7-1] Compounds represented by the general formula (I), their N-oxides, their prodrugs, and their pharmaceuticals in the production of therapeutic agents for suppressing the progression of cancer or infectious diseases, suppressing recurrence, and / or treating them. Use of acceptable salts or solvates thereof;
[7-2] Compounds represented by the general formula (I-1), N-oxides thereof, and pharmaceutically acceptable compounds thereof in the production of therapeutic agents for suppressing the progression of cancer or infectious diseases, suppressing recurrence, and / or treating them. Use of salts or solvates thereof;

[8-1] Other anticancer agents according to the preceding paragraphs [2-3], [3-8] to [3-10], or [3-23] are alkylating agents, platinum preparations, antimetabolites. (For example, antimetabolites, pyridine metabolism inhibitors and purine metabolism inhibitors), ribonucleotide reductase inhibitors, nucleotide analogs, topoisomerase inhibitors, microtubule polymerization inhibitors, microtubule depolymerization inhibitors, antitumor antibiotics , The pharmaceutical composition according to the preceding paragraph [2-3] or the pharmaceutical composition according to the preceding paragraph [3-8] to [3-10] or [3-23], which is one or more agents selected from a cytokine preparation and an antihormonal agent. Agent;
[8-2] The other anticancer agent according to the preceding paragraph [2-3], [3-8] to [3-10] or [3-23] is a molecular target drug, the preceding paragraph [2-3]. ] The pharmaceutical composition or the agent according to the preceding paragraph [3-8] to [3-10] or [3-23];
[8-3] Molecular-targeted agents include ALK inhibitors, BCR-ABL inhibitors, EGFR inhibitors, B-Raf inhibitors, VEGFR inhibitors, FGFR inhibitors, c-Met inhibitors, Axl inhibitors, and Mek inhibitors. Agent, CDK inhibitor, Btk inhibitor, PI3K-δ / γ inhibitor, JAK-1 / 2 inhibitor, TGFbR1 inhibitor, Cancer cell stemness kinase inhibitor, Syk / FLT3 dual inhibitor, ATR inhibitor, Wee1 kinase Inhibitor, multityrosine kinase inhibitor, mTOR inhibitor, HDAC inhibitor, PARP inhibitor, aromatase inhibitor, EZH2 inhibitor, galectin-3 inhibitor, STAT3 inhibitor, DNMT inhibitor, SMO inhibitor, Hsp90 inhibitor , Γ-Tubulin-specific inhibitor, HIF2α inhibitor, glutaminase inhibitor, E3 ligase inhibitor, Nrf2 activator, arginase inhibitor, cell cycle inhibitor, IAP antagonist, anti-Her2 antibody, anti-EGFR antibody, anti- VEGF antibody, anti-VEGFR2 antibody, anti-CD20 antibody, anti-CD30 antibody, anti-CD38 antibody, anti-DR5 antibody, anti-CA125 antibody, anti-DLL4 antibody, anti-fucosyl GM1 antibody, anti-gpNMB antibody, anti-Mesothelin antibody, anti-MMP9 antibody, anti-GD2 Antibodies, anti-c-Met antibody, anti-FOLR1 antibody, anti-Ang2-VEGF bispecific antibody, anti-CD30-CD16A bispecific antibody, anti-CD79b antibody, anti-FAP antibody / IL-2 fusion protein, anti-CEA antibody / One or more agents selected from IL-2 fusion protein, anti-CEA-CD3 bispecific antibody, anti-DLL3 antibody, anti-CD3-CD19 bispecific antibody and anti-CD20-CD3 bispecific antibody. The pharmaceutical composition according to the preceding item [8-2] or the agent according to the preceding item [8-2];
[8-4] The other anticancer agent according to the preceding paragraph [2-3], [3-8] to [3-10] or [3-23] is a cancer immunotherapeutic agent, the preceding paragraph [2]. -3] The pharmaceutical composition or the agent according to the preceding paragraphs [3-8] to [3-10] or [3-23];
[8-5] Cancer immunotherapeutic agents include anti-PD-1 antibody, anti-PD-L1 antibody, PD-1 antagonist, PD-L1 / VISTA antagonist, PD-L1 / TIM3 antagonist, anti-PD-L2. Antibody, PD-L1 fusion protein, PD-L2 fusion protein, anti-CTLA-4 antibody, anti-LAG-3 antibody, LAG-3 fusion protein, anti-Tim3 antibody, anti-KIR antibody, anti-BTLA antibody, anti-TIGIT antibody, anti-VISTA Antibodies, anti-CD137 antibodies, anti-CSF-1R antibodies / CSF-1R inhibitors, anti-OX40 antibodies, anti-HVEM antibodies, anti-CD27 antibodies, anti-GITR antibodies, anti-CD28 antibodies, anti-CCR4 antibodies, anti-B7-H3 antibodies, anti-ICOS Amplifier antibody, anti-CD4 antibody, anti-DEC-205 antibody / NY-ESO-1 fusion protein, anti-SLAMF7 antibody, anti-CD73 antibody, anti-CD122 antibody, anti-CD40 agonist antibody, IDO inhibitor, TLR agonist, adenosine A2A receptor antagonism One or more agents selected from agents, anti-NKG2A antibodies, anti-CSF-1 antibodies, immunopotentiators, IL-15 super agonists, soluble LAG3, CD47 antagonists and IL-12 antagonists, the preceding paragraph [8-4]. ] The pharmaceutical composition or the agent according to the preceding paragraph [8-4];
[8-6] Anti-PD-1 antibodies include Nivolumab, Cemiplimab, Pembrolizumab, Spartanizumab, Tislelizumab, AMP-514, Dostarlimab, Tripalimab, Camrelizumab, Genolimzumab, Sintilimab, STI-A1110, ENUM 388D4, ENUM 244C8 AGEN2034, CS1003, HLX10, BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, Sym021, GB226, SSI-361, JY034, HX008, ABBV181, BCD-100, ISU106, PF-06801591, CX-188, JNJ -The pharmaceutical composition according to the preceding paragraph [8-5] or the agent according to the preceding paragraph [8-5], which is an antibody selected from 63723283 and AB122;
[8-7] Anti-PD-L1 antibodies are Atezolizumab, Avelumab, Durvalumab, BMS-936559, STI-1014, KN035, LY3300054, HLX20, SHR-1316, CS1001, MSB2311, BGB-A333, KL-A167, CK- The pharmaceutical composition according to the preceding paragraph [8-5] or the agent according to the preceding paragraph [8-5], which is an antibody selected from 301, AK106, AK104, ZKAB001, FAZ053, CBT-502, JS003 and CX-072;

[9-1] Compounds represented by the general formula (I), the general formula (II) or the general formula (III), their N-oxides, their prodrugs, their pharmaceutically acceptable salts or theirs. STING agonist containing solvate as an active ingredient;
[9-2] Compounds represented by the general formula (I-1), the general formula (II-1) or the general formula (III-1), their N-oxides, their pharmaceutically acceptable salts or them. STING agonist containing the solvate of STING as an active ingredient;

[10-1] Compounds represented by the general formula (I), the general formula (II) or the general formula (III), their N-oxides, their prodrugs, their pharmaceutically acceptable salts or theirs. IFN-β production inducer containing a solvate as an active ingredient; and [10-2] compounds represented by the general formula (I-1), the general formula (II-1) or the general formula (III-1), the same. An IFN-β production inducer containing an N-oxide compound, a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.

Since the compound of the present invention has operative activity against STING, it can be used as an active ingredient of an agent for suppressing the progression of cancer or an infectious disease, suppressing recurrence, and / or a therapeutic agent.

The antitumor action of the compound of the present invention (the compound shown in Example 1) in the mouse colon cancer cell line MC38 subcutaneous cancer model is shown. Vehicle and the compound of the present invention (n = 6) were administered 7 days after transplantation of MC38, and changes in tumor volume were measured over time until 26 days after transplantation. The antitumor action of the compounds of the present invention (each compound shown in Examples 10, 10 (1) and 10 (2)) in the mouse colon cancer cell line MC38 subcutaneous cancer model is shown. Vehicle and the compound of the present invention (n = 8) were administered 7 days after transplantation of MC38, and changes in tumor volume were measured over time until 28 days after transplantation. The antitumor action of the compounds of the present invention (each compound shown in Examples 10 (3) to 10 (6)) in the mouse colon cancer cell line MC38 subcutaneous cancer model is shown. Vehicle and the compound of the present invention (n = 6) were administered 8 days after transplantation of MC38, and changes in tumor volume were measured over time until 30 days after transplantation.

In the specification of the present invention, examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

In the specification of the present invention, examples of the "C1-4 alkyl group" include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group and a tert-butyl group. ..

In the specification of the present invention, the "C1-5 alkyl group" includes a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group and a pentyl group. , Isopentyl group and 2,3-dimethylpropyl group.

In the specification of the present invention, the "C1 to 3 alkylene groups" are a methylene group, an ethylene group or a propylene group.

In the specification of the present invention, the "C1-4 alkoxy group" includes a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group and the like. Can be mentioned.

In the specification of the present invention, the "C1-4 haloalkyl group" includes, for example, a fluoromethyl group, a chloromethyl group, a bromomethyl group, an iodomethyl group, a difluoromethyl group, a trifluoromethyl group, a 1-fluoroethyl group, and a 2-fluoro group. Ethyl group, 2-chloroethyl group, pentafluoroethyl group, 1-fluoropropyl group, 2-chloropropyl group, 3-fluoropropyl group, 3-chloropropyl group, 4,4,4-trifluorobutyl group and 4- Examples thereof include bromobutyl.

In the specification of the present invention, the "C1-4 haloalkoxy group" includes, for example, a trifluoromethoxy group, a trichloromethoxy group, a chloromethoxy group, a bromomethoxy group, a fluoromethoxy group, an iodomethoxy group, a difluoromethoxy group, and a dibromomethoxy group. Group, 2-chloroethoxy group, 2,2,2-trifluoroethoxy group, 2,2,2-trichloroethoxy group, 3-bromopropoxy group, 3-chloropropoxy group, 2,3-dichloropropoxy group, etc. Can be mentioned.

In the specification of the present invention, examples of the "C3 to 6 cycloalkyl group" include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group.

In the specification of the present invention, examples of the "C3-7 cycloalkyl group" include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group.

In the specification of the present invention, examples of the "C3-7 cycloalkylene group" include a cyclopropylene group, a cyclobutylene group, a cyclopentylene group, a cyclohexylene group and a cycloheptylene group.

In the specification of the present invention, the "C1-4 alkoxycarbonyl group" includes a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an isopropoxycarbonyl group, an n-butoxycarbonyl group, an isobutoxycarbonyl group, and a sec-butoxy. Examples thereof include a carbonyl group and a tert-butoxycarbonyl group.

In the specification of the present invention, examples of the "C5-6 monocyclic carbocycle" include cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene and benzene.

In the specification of the present invention, "5 to 7-membered monocyclic ring" includes, for example, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, benzene, cycloheptane, cycloheptene, cycloheptadiene, pyrrole, oxazole, iso. Oxazole, thiazole, isothiazole, pyrrolin, pyrrolidine, dihydrooxazole, tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole, tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole, imidazole, pyrazole, frazane, oxadiazol, thiazazole , Imidazoline, imidazolidine, pyrazoline, pyrazolidine, dihydroflazan, tetrahydroflazan, dihydrooxazazole, tetrahydrooxazole, dihydrothiazol, tetrahydrothiazol, triazole, triazoline, triazolidine, tetrazol, tetrazolin, tetrazolidine, furan, dihydrofuran, Tetrahydrofuran, oxolane, dioxolan, thiophene, dihydrothiophene, tetrahydrothiophene, dithiolane, pyridine, oxazole, thiazine, dihydropyridine, tetrahydropyridine, piperidine, dihydrooxazine, tetrahydrooxazine, dihydrothiazine, tetrahydrothiazine, morpholine, thiomorpholin, pyrazine, Pyrimidine, pyridazine, oxadiazine, thiadiazine, dihydropyranin, tetrahydropyranin, piperazin, dihydropyramidin, tetrahydropyramidin, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrooxadiazine, tetrahydrooxadiazine, dihydrothiadiazine. , Tetrahydropyranidin, pyran, dihydropyran, tetrahydropyran, oxothian, dioxotian, oxatian, dioxane, thiopyran, dihydrothiopyran, tetrahydrothiopyran, dithian, azepine, diazepine, oxepine, thiepin, oxazepine, oxadiazepine, thiazepine Dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrooxepine, tetrahydrooxepine, perhide Looxepine, dihydrothiepine, tetrahydrothiepine, perhydrothiepine, dihydrooxazepine, tetrahydrooxazepine, perhydrooxazepine, dihydrooxadazepine, tetrahydrooxadizepine, perhydrooxadizepine, dihydrothiazepine , Tetrahydrothiazepine, perhydrothiazepine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine and the like.

In the specification of the present invention, "8 to 10-membered bicycle" includes, for example, pentalene, perhydropentalene, inden, perhydroinden, indan, azulene, perhydroazulene, naphthalene, dihydronaphthalene, tetrahydronaphthalene, perhydro. Naphthalene, thienopyrazole, thienoimidazole, pyrazolotiazole, indole, isoindole, indridin, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, purine, benzoxazole, benzothiazole, benzimidazole, imidazolepyridine, benzofuran, Benzimidazole azole, benzotriazol, indolin, isoindolin, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, Perhydroindazole, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobenzothiazole, perhydrobenzothiazole, dihydrobenzoimidazole, perhydrobenzimidazole, dioxaindane, benzodithiophene, dithianaphthalene, quinoline, isoquinolin, quinolidine, phthalazine, pteridine, Naftilidine, quinoxaline, quinazoline, cinnoline, chromen, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinolin, dihydrophthalazine, tetrahydrophthalazine, perhydrophthalazine, dihydronaphthylidine, tetrahydronaphthylidine, per Hydronaphthylidine, dihydroquinoxaline, tetrahydroquinoxalin, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrocinnoline, tetrahydrocinnoline, perhydrocinnoline, benzoxatian, dihydrobenzoxazine, dihydrobenzothiadin, pyra Dinomorpholin, benzodioxane, chroman, benzoditian and the like.

In the specification of the present invention, "5-6-membered monocyclic heterocycle containing 1 to 4 heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom" includes, for example, pyrrole, oxazole, isooxazole, and the like. Thiazol, isothiazole, pyrrolin, pyrrolidine, dihydrooxazole, tetrahydroxazole, dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole, tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole, imidazole, pyrazole, frazane, oxadiazol, thiadiazol, imidazoline , Imidazolidine, pyrazoline, pyrazolidine, dihydrofrazan, tetrahydrofrazan, dihydrooxazazole, tetrahydroxaziazole, dihydrothiazazole, tetrahydrothiazol, triazole, triazoline, triazolidine, tetrahydropyran, tetrazoline, tetrazolidine, furan, dihydrofuran, tetrahydrofuran, Oxoran, dioxoran, thiophene, dihydrothiophene, tetrahydrothiophene, dithiolane, pyridine, oxazine, thiazine, dihydropyridine, tetrahydropyran, piperidine, dihydrooxazine, tetrahydropyran, dihydrothiazine, tetrahydropyran, morpholine, thiomorpholin, pyrazine, pyrimidine, Pyridazine, oxadiazine, thiadiadin, dihydropyran, tetrahydropyran, piperazin, dihydropyranidin, tetrahydropyranidin, perhydropyranidin, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroxadazine, tetrahydropyranidin, dihydrothiadiazine, tetrahydro Examples thereof include thiadiadine, pyran, dihydropyran, tetrahydropyran, oxothian, dioxotian, oxatian, dioxane, thiopyran, dihydrothiopyran, tetrahydropyran and dithian.

In the specification of the present invention, examples of "5- to 6-membered monocyclic aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom" include pyrol, imidazole and triazole. , Tetrazole, pyrazole, furan, thiophene, oxazole, isoxazole, thiazole, isothazole, frazane, oxadiazol, thiazazole, pyridine, pyrazine, pyrimidine, pyridazine and the like.

In the specification of the present invention, examples of the "5- to 6-membered monocyclic aromatic nitrogen-containing heterocycle containing 1 to 4 nitrogen atoms and no other heteroatoms" include pyrrole, imidazole, triazole, and the like. Examples thereof include tetrazole, pyrazole, pyridine, pyrazine, pyrimidine and pyridazine.

In the specification of the present invention, examples of the "3- to 7-membered monocyclic non-aromatic heterocycle" include, for example, oxylan, aziridine, thiirane, azetidine, oxetane, thietan, pyrrolin, pyrrolidine, imidazoline, imidazolidine, triazoline, and the like. Triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dihydrooxazole, tetrahydrooxazole, dihydroisoxazole, tetrahydroisoxazole, dihydrothiazole, tetrahydrothiazole, dihydroisothiazole, tetrahydroisothiazole, dihydro Frazan, tetrahydropyran, dihydrooxadiazol, tetrahydrooxadiazole, dihydrothiasizole, tetrahydrothiasazole, oxoran, dioxolan, dithiolane, pyran, thiopyran, oxazine, oxadiazine, thiazine, thiadiazine, dihydropyridine, tetrahydropyran, piperidine, dihydropyrazine, Tetrahydropyran, piperazin, dihydropyranidin, tetrahydropyranzin, perhydropyrimidine, dihydropyridazine, tetrahydropyranidin, perhydropyridazine, dihydropyran, tetrahydropyran, dihydrothiopyran, tetrahydropyran, dihydrooxazine, tetrahydrooxazine, dihydrooxadiadin, Tetrahydropyranidein, dihydrothiadine, tetrahydropyrane, dihydrothiazine, tetrahydropyranidin, morpholine, thiomorpholin, oxotian, dioxotian, oxatian, dioxane, dithione, azepine, diazepine, oxepine, thiepin, oxazepine, oxadiazepine, Thiazepine, thiadiazepine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrooxepin, tetrahydrooxepin, perhydrooxepin, dihydrotiepine, tetrahydropyran , Perhydrothiepine, dihydrooxazepine, tetrahydropyranzepine, perhydrooxazepine, dihydrooxadizepine, tetrahydroxaziazepine, perhydrooxadizepine, dihydrothiazepine, tetrahydrothiazepine, perhydrothiazepine , Dihydrochi Examples thereof include Asiazepine, Tetrahydrothiazepine and Perhydrothiazepine.

In the specification of the present invention, "as a result of decomposition in vivo, a compound represented by the general formula (I), its N-oxide form, a pharmaceutically acceptable salt thereof or a solvate thereof is produced. Examples of the "group" include a group defined as ^RFR .

The ring A in the general formulas (I), (I-1), (II) or (II-1) of the present invention is preferably 1 to 4 heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom. A 5- to 6-membered monocyclic aromatic heterocycle containing, more preferably pyrazole, triazole (eg, 1,2,3-triazole and 1,2,4-triazole), tetrazole, oxazole, isooxazole, It is imidazole, thiazole or isothiazole, more preferably pyrazole, while the ring B of the general formula (I) or (I-1) of the present invention is preferably (i) C5-6 monocyclic carbocycle. Alternatively, (ii) a 5- to 6-membered monocyclic heterocycle containing 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur atoms, more preferably a benzene ring.

Further, in the general formula (I) or (I-1) of the present invention, Z is preferably an oxygen atom, Y is preferably −CH =, and X is preferably a nitrogen atom.

The L ² in the general formula (I) and the like, the formula (Ib), the general formula (I-1) and the like or the formula (Ib-1) of the present invention is preferably a bond or a C1 to 3 alkylene group, and more preferably. a bond, preferably a ^{L 1, -O -, - CONH} -, - CO -, - CO 2 -, - S -, - SO 2 - or a -SO-, more preferably, -CONH - (where the left side of the group is attached to the ring B.), - CO -, - CO 2 -, - S -, - SO 2 - or a -SO-, preferably a hydrogen atom as ^{R 1,} It is a hydroxyl group, a C1-4 alkyl group or a carboxy group, more preferably a hydrogen atom or a C1-4 alkyl group, even more preferably a hydrogen atom, a methyl group, an ethyl group or an n-propyl group, R ² and R ^2c is preferably a nitro group and NR ^2a R ^2b and NR ^2d R ^2e , respectively, more preferably an amino group, and R ³ is preferably a hydrogen atom, a halogen atom or a hydroxyl group, more preferably a halogen atom. Is.

The m in the general formula (I) and the like, the formula (Ib), the general formula (I-1) and the like or the formula (Ib-1) of the present invention is preferably 1 and preferably zero or 1 as p and pa. , More preferably zero. The n in the formula (Ib) or (Ib-1) or the general formula (II), (II-1), (III) or (III-1) of the present invention is preferably 2 or 1.

R ^2a , R ⁴ and R ⁶ in the general formula (I) and the like of the present invention are preferably hydrogen atoms, and R ^2d , R ^4a and R ^{6a in} the general formula (I-1) and the like are preferably hydrogen atoms. Alternatively, it is a phosphonooxyalkyl group, and the phosphonooxyalkyl group is preferably -CH ₂ OP (= O) (OH) ₂ , -CHCH ₃ OP (= O) (OH) ₂ or -CH ₂ OP ( = O) (OH) (OCH ₂ OCO ₂ CH (CH ₃ ) ₂ ), more preferably −CH ₂ OP (= O) (OH) ₂ . However, two or more of R ^2d , R ^4a and R ^6a do not represent a phosphonooxyalkyl group at the same time.

As W in the formula (Ib), the formula (Ib-1), the general formula (II), the general formula (II-1), the general formula (III) or the general formula (III-1) of the present invention, preferably −CH = And V is preferably −CH =.

The U in the formula (Ib), formula (Ib-1), general formula (II) or general formula (II-1) of the present invention is preferably a carbon atom.

The T in the general formulas (I), (I-1), (II) or (II-1) of the present invention is preferably a nitrogen atom.

The compounds represented by the general formula (I) of the present invention, their N-oxides, their prodrugs, their pharmaceutically acceptable salts or their solvates are preferably represented by the general formula (II). Compounds, N-oxides thereof, prodrugs thereof, pharmaceutically acceptable salts thereof or solvates thereof, more preferably compounds represented by the general formula (III), N-oxides thereof. The bodies, their prodrugs, their pharmaceutically acceptable salts or their solvates.

Further, preferably as a compound represented by the general formula (I), an N-oxide compound thereof, a prodrug thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, for example, the above-mentioned item [26]. Examples thereof include compounds (1) to (35), their N-oxides, their prodrugs, their pharmaceutically acceptable salts or their solvates.

Further, as a compound represented by the general formula (I-1) of the present invention, an N-oxide compound thereof, a pharmaceutically acceptable salt thereof or a solvate thereof, the compound represented by the general formula (II-1) is preferably used. The compounds shown, their N-oxides, their pharmaceutically acceptable salts or solvates thereof, more preferably the compounds represented by the general formula (III-1), their N-oxides, They are pharmaceutically acceptable salts or solvates thereof.

Further, the compound represented by the general formula (I-1), its N-oxide form, a pharmaceutically acceptable salt thereof or a solvate thereof is preferable, for example, according to the above item [1-33]. Examples thereof include the compounds of 1) to (44), their N-oxides, their pharmaceutically acceptable salts or their solvates. Further, as a solvent mixture of the compounds (1) to (44) described in the preceding item [1-33], the compounds (1) to (44) described in the preceding item [1-33] or their pharmaceuticals are preferable. A hydrate of an acceptable salt (eg, an alkali metal salt (eg, lithium salt, sodium salt, potassium salt, etc.)).

[Isomer]
Unless otherwise specified in the present invention, isomers include all of them. For example, alkyl groups include linear and branched chains. Furthermore, geometric isomers (E-form, Z-form, cis-form, trans-form) in double bonds, rings, and fused rings, optical isomers due to the presence of asymmetric carbon atoms (R, S-form, α, β arrangement, etc.) Enantiomers, diastereomers), optically active (D, L, d, l), polar bodies (high polar, low polar) by chromatograph separation, equilibrium compounds, rotational isomers, these Arbitrary proportions of mixtures, racemic mixtures are all included in the present invention. In addition, the present invention also includes all isomers of tautomers.

Further, the optical isomer in the present invention is not limited to 100% pure, and may contain less than 50% of other optical isomers.

In the present invention, unless otherwise specified, symbols will be apparent to those skilled in the art.

Indicates that it is connected to the other side of the paper (that is, α arrangement).

Indicates that it is connected to the front side of the paper (that is, β arrangement).

Indicates that it is an α configuration, a β configuration, or a mixture of any ratio thereof.

Represents a single bond or a double bond.

[N-oxide body]
The compound represented by the general formula (I) or the like or the general formula (I-1) or the like can be made into an N-oxide compound by a known method. The N-oxide compound represents a compound in which the nitrogen atom of the compound represented by the general formula (I) or the like or the general formula (I-1) or the like is oxidized. Further, these N-oxides are pharmaceutically acceptable as the prodrug as described in the following [Prodrug] item, the following [Salt] item and the following [Solvate] item. It may be a salt or a solvate thereof.

[Prodrug]
The compound represented by the general formula (I) or the like or its N-oxide form can also be made into a prodrug by a known method. The prodrug refers to a compound represented by the general formula (I) or the like or a compound converted into an N-oxide compound thereof by a reaction with an enzyme, gastric acid or the like in a living body. For example, a compound represented by the general formula (I-1) or the like in which any one of R ^2d , R ^4a and R ^6a is the above R ^FR or an N-oxide compound thereof is represented by the general formula (I) or the like. It can be administered as a prodrug of the compound or its N-oxides, preferably as the prodrug, for example, (14), (18), (19), (32) according to the preceding paragraph [1-33]. , (37)-(39), (41) and (42). The compound represented by the general formula (I) or the prodrug of its N-oxide form is described in Hirokawa Shoten, 1990, "Development of Pharmaceuticals", Vol. 7, "Molecular Design", pp. 163 to 198. It may be changed to the corresponding compound represented by the general formula (I) or the like or its N-oxide compound under physiological conditions.

As other prodrugs of the compound represented by the general formula (I) or the like or its N-oxide compound, for example, the compound represented by the general formula (I) or the like or its N-oxide compound contains 1 to 4 nitrogens. In the case of having a 5- to 6-membered monocyclic aromatic nitrogen-containing heterocycle containing an atom and not containing other heteroatoms, the nitrogen atom on the nitrogen-containing heterocycle is acylated, alkylated or phosphorylated. (For example, the nitrogen atom on the nitrogen-containing heterocycle of the compound represented by the general formula (I) or the like is ecosanoyylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-). Dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated or tert-butylated compounds, etc.), compounds represented by the general formula (I), etc. When the compound has an amino group, the compound in which the amino group is acylated, alkylated or phosphorylated (for example, the amino group of the compound represented by the general formula (I) or the like is ecosanoyylated, alanylated, pentylaminocarbonylated, etc. (5-Methyl-2-oxo-1,3-dioxolen-4-yl) methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, acetoxymethylated or tert-butylated compounds Etc.), when the compound represented by the general formula (I) or the like has a hydroxyl group, the compound in which the hydroxyl group is acylated, alkylated, phosphorylated or booxide (for example, the compound represented by the general formula (I) or the like) Examples thereof include compounds in which the hydroxyl groups are acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated, etc.), and the compounds represented by the general formula (I) and the like are carboxy groups. When the compound has an esterified or amidated carboxy group (for example, the carboxy group of the compound represented by the general formula (I) or the like is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl ester Compound, pivaloyloxymethyl esterification, 1-{(ethoxycarbonyl) oxy} ethyl esterification, phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification , 1-{[(cyclohexyloxy) carbonyl] oxy} ethyl esterified or methylamided compounds, etc.) I can get rid of it. These compounds can be produced by methods known per se. In addition, the prodrug of the compound represented by the general formula (I) or the like or its N-oxide is further pharmaceutically as described in the following [salt] item and the following [solvate] item. It may be an acceptable salt or solvate.

[salt]
The compound represented by the general formula (I) or the like, its N-oxide form or a prodrug thereof, and the compound represented by the general formula (I-1) or the like or its N-oxide form are equivalent pharmaceuticals by a known method. Can be converted to an acceptable salt. Here, examples of the pharmaceutically acceptable salt include alkali metal salts (for example, lithium salt, sodium salt, potassium salt, etc.) and alkaline earth metal salts (for example, calcium salt, magnesium salt, barium salt, etc.). , Ammonium salts, organic amine salts (eg, aliphatic amine salts (eg, methylamine salts, dimethylamine salts, cyclopentylamine salts, trimethylamine salts, triethylamine salts, dicyclohexylamine salts, monoethanolamine salts, diethanolamine salts, triethanolamine) Salts, procaine salts, meglumine salts, diethanolamine salts, tris (hydroxymethyl) aminomethane salts and ethylenediamine salts, etc.), aralkylamine salts (eg, benzylamine salts, phenethylamine salts, N, N-dibenzylethylenediamine salts and venetamine salts, etc.) ), Heterocyclic aromatic amine salts (eg, piperidine salt, pyridine salt, picolin salt, quinoline salt, isoquinolin salt, etc.), quaternary ammonium salt (eg, tetramethylammonium salt, tetraethylamonium salt, benzyltrimethylammonium salt, etc.) , Benzyltriethylammonium salt, benzyltributylammonium salt, methyltrioctylammonium salt, tetrabutylammonium salt, etc.), basic amino acid salt (eg, arginine salt, lysine salt, etc.) and N-methyl-D-glucamine salt, etc. Acid adduct salts (eg, mineral salts (eg, hydrochlorides, hydrobromates, hydroiodates, sulfates, phosphates and nitrates, etc.) and organic acid salts (eg, acetates, trifluoros) Acetate, lactate, tartrate, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethion Acid salts, gluclon salts, glucone salts, etc.)) and the like. The pharmaceutically acceptable salt is preferably water-soluble.

In particular, in the compound represented by the general formula (I-1) or the like in which any one of R ^2d , R ^4a and R ^6a is the above-mentioned phosphonooxyalkyl group, for example, a compound forming a salt with the same group is used. , The above-mentioned alkali metal salt, the above-mentioned alkaline earth metal salt, magnesium salt, zinc salt, ammonium salt, organic amine salt and the like, and among them, preferable alkali metal salts are sodium salt and potassium salt. The preferred alkaline earth metal salt is a calcium salt, and the preferred organic amine salt is a basic amino acid salt (eg, arginine salt (eg, L-arginine salt), lysine salt (eg, L-lysine salt), etc. ), Megrumine salt, tris (hydroxymethyl) aminomethane salt and the like.

[Solvate]
Compounds represented by the general formula (I) and the like, N-oxides thereof, prodrugs thereof or pharmaceutically acceptable salts thereof and compounds represented by the general formula (I-1) and the like, N-oxides thereof. Alternatively, their pharmaceutically acceptable salts can also be converted to solvates by known methods. The solvate is preferably low toxicity and water soluble. Suitable solvates include, for example, solvates with water, alcoholic solvents (eg, ethanol, etc.). Here, the hydrate may take the form of, for example, a polyhydrate such as monohydrate to pentahydrate or a low hydrate such as a hemihydrate, and the compound of the present invention may be used. Examples of the hydrate form include monohydrate, dihydrate, trihydrate and 2-3 hydrate. In addition, the forms of these hydrates include clathrate hydrates. These hydrates are compounds represented by the general formula (I) or the like, N-oxides thereof, prodrugs thereof or pharmaceutically acceptable salts thereof or compounds represented by the general formula (I-1) or the like. , The N-oxide compound or a pharmaceutically acceptable salt thereof can be obtained, for example, by precipitating from a hydrous organic solvent.

[Co-crystal]
Compounds represented by the general formula (I) and the like, N-oxides thereof, prodrugs thereof, pharmaceutically acceptable salts thereof or solvates thereof and compounds represented by the general formula (I-1) and the like. , The N-oxides, their pharmaceutically acceptable salts or their solvates can form co-crystals with suitable co-crystal forming agents. As the co-crystal, a pharmaceutically acceptable one formed with a pharmaceutically acceptable co-crystal forming agent is preferable. A co-crystal is defined as a crystal in which two or more different molecules are formed by an intermolecular interaction different from an ionic bond. Further, the co-crystal may be a complex of a neutral molecule and a salt. Co-crystals can be prepared by known methods, such as melt crystallization, recrystallization from a solvent or physical grinding of the components together. Suitable co-crystal forming agents include those described in Pamphlet 2006/007448, such as 4-aminobenzoic acid, 4-aminopyridine, adenine, alanine, acetylsalicylic acid and the like.

[Radioactive isotope]
Compounds represented by the general formula (I) and the like, N-oxides thereof, prodrugs thereof, pharmaceutically acceptable salts thereof or solvates thereof and compounds represented by the general formula (I-1) and the like. its N- oxide thereof, a pharmaceutically acceptable salt or solvate thereof is isotopes ^{(e.g., 2 H, 3 H, 11} C, 13 C, 14 C, 13 N, 15 N, ^It may be labeled with ¹⁵ O, ¹⁷ O, ¹⁸ O, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I, ¹²⁵ I, etc.). For example, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ^{7 in the} general formula (I) or R ¹ , R ^2c , R ³ , R ^4a , R in the general formula (I-1). ⁵ , R ^6a and R ⁷ include compounds in which all or part of the hydrogen atoms constituting one or more groups are replaced with heavy water atoms or triple hydrogen atoms, for example, 4- (4-amino- Examples thereof include 2-fluoro-5- (methoxy-d ₃ ) phenyl) -7- (1H-pyrazol-4-yl) isoxazolo [4,5-c] pyridine-3-amine. In addition, in this specification, "methyl-d ₃ " and "methoxy-d ₃ " represent a triduteiomethyl group and a triduteliomethoxy group, respectively.

[Method for producing the compound of the present invention]
The compound of the present invention is a known method, for example, the method described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 2nd Edition (Richard C. Larock, John Wiley & Sons Inc, 1999), the method or practice shown below. It can be produced by appropriately improving the methods shown in the examples and using them in combination.

Among the compounds represented by the general formula (I) and the like, the general formula (IV)

[In the formula, all symbols have the same meaning as above. ] Can be produced by the method represented by the following reaction step formula 1.

[In the formula, Pg represents an amino protective group (eg, tert-butoxycarbonyl group, benzyloxycarbonyl group, fluorenylcarbonyl group, trityl group, o-nitrobenzenesulphenyl group, acetyl group, etc.) and represents R'. Each independently represents a hydrogen atom, a C1-5 alkyl group, a C3-6 cycloalkyl group, a hydroxyl group or a halogen atom, where if R'represents a C1-5 alkyl group, the two R's Adjacent oxygen and boron atoms may be combined to form a dioxaborolan ring, with other symbols having the same meanings as above. ]

The coupling reaction 1 in the reaction step formula 1 can be carried out by a known Suzuki coupling reaction, for example, 0.01 to 100 mol% palladium catalyst (for example, tetrakistriphenylphosphine palladium, bis (triphenylphosphine)). ) Palladium (II) dichloride, tris (dibenzylideneacetone) dipalladium, palladium acetate, palladium acetylacetoneate, [1,1'-bis (diphenylphosphine) ferrocene] dichloropalladium dichloromethane complex or bis [di-tert-butyl ( 4-Dimethylaminophenyl) phosphine] palladium, etc.) and 0.01-400 mol% phosphine ligands (eg, triphenylphosphine, tritert-butylphosphine, tricyclohexylphosphine or di (1-adamantyl) -n-butyl In the presence or absence of phosphine, etc.), organic solvents (eg, dichloromethane, chloroform, dioxane, ethyl acetate, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, dimethylformamide, N-methylpyrrolidone, etc.) alone or in a mixed solvent with water, In the presence or absence of 1-10 equal amounts of bases (eg, potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium phosphate, potassium triethylamine phosphate or N, N-diisopropylethylamine, etc.), It is carried out at 0 to 200 ° C. in the presence of 1 to 10 equal volumes of boric acid reagent.

Coupling reaction 1 can also be carried out by a known coupling reaction using an organic metal reagent. For example, Negishi reaction using a zinc reagent instead of boric acid reagent and tin reagent instead of boric acid reagent. The Still reaction to be used, the Hiyama coupling using a silicon reagent instead of the boric acid reagent, the Grinyard reagent instead of the boric acid reagent, and the Kumada reaction using a nickel catalyst instead of the palladium catalyst are also performed.

The coupling reaction 2 in the reaction step formula 1 is also carried out by a known Suzuki coupling reaction, Negishi reaction, Still reaction, Hiyama coupling, Kumada reaction and the like.

The deprotection reaction in Reaction Step 1 can be carried out by a known deprotection reaction under acidic conditions, for example, organic solvents (eg, dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropyl alcohol, tetrahydrofuran or Organic acids (eg, acetic acid, trifluoroacetic acid, methanesulfonic acid or p-tosylic acid, etc.) or inorganic acids (eg, hydrochloric acid, sulfuric acid, etc.) or mixtures thereof (eg, hydrogen bromide / acetic acid, etc.) in anisole, etc. ), In the presence or absence of 2,2,2-trifluoroethanol, at 0-100 ° C.

The compound represented by the general formula (I-1) or the like in which none of R ^2d , R ^4a and R ^6a represents the above R ^FR can be produced by the method shown in the above reaction step formula 1. it can.

Further, among the compounds represented by the general formula (I-1) and the like, the general formula (V)

[In the formula, R ^4b represents − (CR ^Fb ₂ ) _q OP (= O) (OR ^Fa ′) ₂ , and R ^Fa ′ independently represents a hydrogen atom, a C1 to 4 alkyl group, and C3 to. 6 Cycloalkyl group, − (CH ₂ ) ₂ OH or −CH ₂ OCO ₂ CH (CH ₃ ) ₂ and other symbols have the same meanings as above. ], The compound represented by the general formula (IV) shall be subjected to the following alkylation reaction, and if R ^{Fa'is a} protecting group, it shall be subjected to a deprotection reaction if necessary. Can be done.

[In the formula, X ¹ represents a halogen atom, and other symbols have the same meanings as described above. ]

Here, the alkylation reaction is known, for example, in an organic solvent (for example, dichloromethane, chloroform, dioxane, ethyl acetate, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc.). , Inorganic bases (potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide, etc.) or organic bases (eg, triethylamine, N, N-diisopropylamine lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis (eg, triethylamine, N, N-diisopropylamine) In the presence of trimethylsilyl amide, potassium bis (trimethylsilyl) amide, tert-butylimino-tris (dimethylamino) phosphorane, tert-butylimino-tri (pyrrolidino) phosphorane or 1,4-diazabicyclo [2.2.2] octane, etc.) , X ¹ (CR ^Fb ₂ ) _q OP (= O) (OR ^Fa ') ₂ is reacted with the compound represented by the general formula (IV). Further, the deprotection reaction of ^'the R ^Fa when is a protecting ^group' R ^Fa also known, for example, a known deprotection reaction or palladium in acidic conditions - even in a hydrogenation reaction in the presence of such carbon catalyst Can be carried out. When R ^{Fa'represents} a protecting group, it corresponds to a protecting group of a hydroxyl group, for example, a methyl group, a trityl group, a methoxymethyl group, a 1-ethoxyethyl group, a methoxyethoxymethyl group, a 2-tetrahydropyranyl group, and the like. Trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, acetyl group, pivaloyl group, benzoyl group, benzyl group, p-methoxybenzyl group, allyloxycarbonyl group or 2,2,2- Examples thereof include a trichloroethoxycarbonyl group. Further, the hydrogenation reaction in the presence of a palladium-carbon catalyst or the like is carried out in an organic solvent (for example, methanol, ethanol, tetrahydrofuran, dioxane, ethyl acetate, isopropyl alcohol, etc.) in a hydrogen gas atmosphere of 1 to 20 atm. It is carried out at room temperature to 120 ° C. in the presence of 0.01 to 100 mol% of catalyst (eg, palladium-carbon, platinum-carbon, palladium-carbon hydroxide or rhodium-carbon, etc.).

The compound represented by the general formula (IV-4) in the reaction step formula 1 can be produced by the method represented by the following reaction step formula 2.

The lithium reaction in the reaction step formula 2 can be carried out by a known method, for example, an organic solvent (for example, tetrahydrofuran, diethyl ether, dioxane, dichloromethane, dichloroethane, n-hexane or toluene or a mixed solvent thereof and the like. ), A base (eg, lithium diisopropylamide, n-butyllithium, tert-butyllithium, etc.) is reacted at −78 ° C. to room temperature, carbon dioxide (eg, carbon dioxide gas, dry ice, etc.) is added, and − It is carried out by reacting at 78 ° C. to room temperature.

The amidation reaction in Reaction Step 2 can be carried out by a known method, for example, in an organic solvent (for example, chloroform, dichloromethane, diethyl ether, tetrahydrofuran or dimethoxyethane, etc.) or in the absence of a solvent. The reaction was carried out with an agent (eg, oxalyl chloride or thionyl chloride, etc.) at -78 ° C to reflux temperature, and the obtained acid halide was used as a base (eg, pyridine, triethylamine, dimethylaniline, dimethylaminopyridine or N, N-diisopropyl). It is carried out by adding ammonia (for example, ammonia gas, ammonia water, ammonia methanol solution, etc.) in the presence or absence of (ethylamine, etc.) and reacting at −78 ° C. to reflux temperature.

The dehydration reaction in Reaction Step 2 can be carried out by a known method, for example, in an organic solvent (eg, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, dimethoxyethane, etc.) or in the absence of a solvent, for example, a base (eg, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, dimethoxyethane, etc.). , Pyridine, triethylamine, dimethylaniline, N, N-dimethylaminopyridine or N, N-diisopropylethylamine, etc. in the presence or absence of dehydrating agents (eg, thionyl chloride, trifluoroacetic anhydride, acetic anhydride, dipentoxide, etc.) It is carried out by reacting in the presence of phosphorus or (methoxycarbonylsulfamoyl) triethylammonium hydroxide intramolecular salt, etc. at −78 ° C. to reflux temperature.

The nucleophilic aromatic substitution reaction in Reaction Step 2 can be carried out by a known method, for example, an organic solvent (for example, N, N-dimethylacetamide, N, N-dimethylformamide, tetrahydrofuran, acetonitrile, 2). -In propanol or dimethyl sulfoxide or a mixed solvent thereof, etc.), 1 to 10 equal amounts of acetonitrile, base (eg, tert-butoxypotassium, tert-butoxysodium, potassium carbonate, cesium carbonate, sodium hydrogencarbonate or tripotassium phosphate, etc.) It is carried out by reacting at room temperature to 120 ° C. in the presence of potassium, etc.).

The deprotection reaction in the reaction step formula 2 can be carried out by a known method, for example, a deprotection reaction under acidic conditions. For example, in an organic solvent (eg, dichloromethane, chloroform, dioxane, ethyl acetate, methanol, isopropyl alcohol, tetrahydrofuran or anisole, etc.), an organic acid (eg, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.) or It is carried out at 0-100 ° C. in the presence or absence of 2,2,2-trifluoroethanol in an inorganic acid (eg, hydrochloric acid or sulfuric acid, etc.) or a mixture thereof (eg, hydrogen bromide / acetic acid, etc.).

The bromization reaction in the reaction step formula 2 can be carried out by a known method, for example, in an organic solvent (for example, dichloromethane, chloroform, tetrahydrofuran, acetonitrile, dioxane, ethyl acetate, acetic acid, etc.), 1 to 10 and the like. Amount of brominating agent (eg, trimethylsilyl bromide (TMSBr), bromine, hydrobromic acid or phosphorus tribromide, etc.) and 0.1 to 100 mol% catalyst (eg, copper (II) bromide or lithium bromide, etc.) ) In the presence or absence of) at −78 ° C. to 100 ° C.

In each reaction herein, the compound used as a starting material or the compound or reagent to be added, for example, the compound represented by the general formula (IV-3) or the general formula (IV-5) and the alkylation reaction or reaction. The compound used in Step Formula 2 can be produced according to a known method or a known method or a method described in Examples.

Among the compounds used in the present invention, the compound having optical activity is produced by using a starting material or a reagent having optical activity, or a racemic production intermediate is optically resolved, and then the compound used in the present invention is obtained. It can also be produced by derivation or by optical resolution of a racemic compound. This method of optical resolution is known. For example, a salt / complex or the like is formed with another optically active compound, recrystallized, and then the target compound is isolated or directly using a chiral column or the like. Examples include a method of separation.

In each of the reactions herein, the reaction involving heating can be carried out using a water bath, an oil bath, a sand bath or a microwave, as will be apparent to those skilled in the art.

In each reaction in the present specification, a solid-phase supporting reagent supported on a high molecular polymer (for example, polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) may be used as appropriate.

In each reaction herein, the reaction product is prepared by conventional purification means, such as distillation under normal pressure or reduced pressure, high speed liquid chromatography with silica gel or magnesium silicate, thin layer chromatography, ion exchange resins. It can be purified by a scavenger resin or a method such as column chromatography, washing or recrystallization. Purification may be performed on a reaction-by-reaction basis or after the completion of several reactions.

[toxicity]
The toxicity of the compound of the present invention is sufficiently low, and it can be safely used as a pharmaceutical product.

[Application to pharmaceutical products]
Since the compound of the present invention has operative activity against STING, it can be formulated as an effective progression inhibitory, recurrence inhibitory or therapeutic agent for cancer or infectious disease.

In addition, in this specification, "cancer treatment" means, for example, (a) to reduce the growth of cancer cells, (b) to reduce the symptoms caused by cancer, and thus the quality of life of cancer patients. To improve (c) reduce the dose of other anticancer agents or cancer treatment aids already administered, and / or (d) to prolong the survival of cancer patients. Including treatments In addition, "suppressing the progression of cancer" means delaying the progression of cancer, stabilizing the symptoms related to cancer, and slowing the progression of the symptoms. By "suppressing recurrence" is meant prophylactically suppressing cancer recurrence in a patient whose cancer lesion has been completely or substantially eliminated or removed by cancer treatment or surgical resection of the cancer.

Furthermore, the compounds of the present invention are (a) cancer patients whose therapeutic effect with other anticancer agents is insufficient or insufficient, or cancer patients who have worsened after treatment with other anticancer agents, and (b) curative or unresectable. , Patients with metastatic, recurrent, refractory and / or distant metastatic cancer, (c) TPS or CPS is 50% or more, 25% or more, 10% or more, 5% or more or 1% or more. Patients, (d) cancer patients with MSI-H or dMMR, (e) patients with BRAF V600E mutation-positive malignant melanoma or non-small cell lung cancer, (f) EGFR gene mutation positive or ALK fusion gene positive It may be prescribed to patients with cancer who have a high frequency of (g) TMB.

On the other hand, the compounds of the present invention include (a) cancer patients who have not been treated with other anticancer agents, and (b) TPS or CPS of less than 50%, less than 25%, less than 10%, less than 5%. Or less than 1% of cancer patients, (c) patients with cancer without MSI-H and / or dMMR, or with MSI-L, (d) BRAF V600 wild-type malignant melanoma or non-small More demanding prescription for patients with cell lung cancer, (e) patients with non-small cell lung cancer who are negative for EGFR gene mutations and / or ALK fusion genes, or (f) patients for cancer with low frequency of TMB There is also.

It can also be prescribed as neoadjuvant therapy to prevent recurrence or metastasis after surgical resection of the cancer or neoadjuvant therapy given before surgical resection.

Here, as the "other anticancer agent", the anticancer agent described in the item of "combination or combination drug" below, that is, an alkylating agent, a platinum preparation, an antimetabolite (for example, folic acid metabolism) Antagonists, pyridine metabolism inhibitors and purine metabolism inhibitors), ribonucleotide reductase inhibitors, nucleotide analogs, topoisomerase inhibitors, microtube polymerization inhibitors, microtube depolymerization inhibitors, antitumor antibiotics, cytokine preparations, anti Examples thereof include agents exemplified as hormonal agents, molecular-targeted agents and cancer immunotherapeutic agents. In addition, "the therapeutic effect of other anticancer agents is insufficient or insufficient" means, for example, "stable (SD)" or "stable (SD)" even by treatment with existing anticancer agents in the tumor contraction effect determination RECIST. There are cases where it is determined to be "progress (PD)".

Cancers for which the compound of the present invention is targeted for progression suppression, recurrence suppression and / or treatment include any solid cancer and blood cancer, and among solid cancers, epithelial cell cancer includes, for example, malignant melanoma. (For example, malignant melanoma in the skin, oral mucosal epithelium or in the orbit), non-small cell lung cancer (eg, flat non-small cell lung cancer and non-flat non-small cell lung cancer), small cell lung cancer, head and neck cancer (eg, oral) Cancer, nasopharyngeal cancer, mesopharyngeal cancer, hypopharyngeal cancer, laryngeal cancer, salivary adenocarcinoma and tongue cancer), renal cell cancer (eg, clear cell renal cell cancer), breast cancer, ovarian cancer (eg, serous ovarian cancer) And ovarian clear cell adenocarcinoma), nasopharyngeal cancer, uterine cancer (eg, cervical cancer and uterine body cancer), anal cancer (eg, anal duct cancer), colon cancer (eg, MSI-H and / or dMMR positive colon) Cancer), rectal cancer, colon cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer, esophagogastric junction cancer, pancreatic cancer, urinary epithelial cancer (eg bladder cancer, upper urinary tract cancer, urinary tract cancer, renal pelvis cancer and urinary tract cancer) ), Prostate cancer, oviduct cancer, primary peritoneal cancer, malignant pleural mesenteric tumor, bile sac cancer, bile duct cancer, biliary tract cancer, skin cancer (eg, vine malignant melanoma and Mercel cell carcinoma), testicular cancer (embryonic cell) Tumors), vaginal cancer, genital pudendal cancer, penis cancer, small intestine cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, spinal tumor, neuroblastoma, myeloma, ocular retinal blastoma, neuroendocrine Examples include tumors, brain tumors (eg, glioma (eg, glioma and glioma) and meningeal carcinoma) and squamous cell carcinoma.

Among solid cancers, sarcomas include bone and soft tissue sarcomas (eg, Ewing's sarcoma, pediatric rhabdomyosarcoma, uterine body smooth sarcoma, chondrosarcoma, lung sarcoma, osteosarcoma, and congenital fibrosarcoma). Examples include Kaposi sarcoma.

Hematological cancers include, for example, multiple myeloma, malignant lymphoma (eg, non-hodgkin lymphoma (eg, follicular lymphoma, precursor B-cell lymphoblastic lymphoma, chronic B lymphocytic leukemia, nodal marginal zone)). B-cell lymphoma, diffuse large-cell B-cell lymphoma, MALT lymphoma, primary splenic marginal zone B-cell lymphoma, hairy cell leukemia, primary mediastinal large-cell B-cell lymphoma, barkit lymphoma, mantle cell Lymphoma, mycobacterial sarcoma, Cesarly syndrome, chronic or acute lymphocytic leukemia, precursor T-cell lymphoblastic lymphoma, chronic T-lymphoma, large-granular T-cell leukemia, large-granule NK-cell leukemia, peripheral T-cell lymphoma, extranodal NK / T-cell lymphoma, adult T-cell leukemia, vascular central lymphoma, intestinal T-cell lymphoma, Hodgkin-like / Hodgkin-related undifferentiated large-cell lymphoma, B-cell lymphoblastic leukemia, T-cell Lymphomacytic leukemia and lymphoplasmacytic lymphoma) and Hodgkin lymphoma (eg, classical Hodgkin lymphoma and nodular lymphocyte-dominant Hodgkin lymphoma) and leukemia (eg, acute myeloid leukemia and chronic myeloid leukemia), central Examples include primary malignant lymphoma of the nervous system, myelodysplasia syndrome and myeloid proliferation syndrome.

Furthermore, cancers for which the compounds of the present invention are targeted for progression suppression, recurrence suppression and / or treatment include childhood cancers and cancers of unknown primary origin.

Infectious diseases for which the compounds of the present invention are targeted for progression suppression, recurrence suppression and / or treatment include symptoms resulting from viral infections, parasitic infections, bacterial infections or fungal infections.

Viral infections include, for example, adenovirus, arenavirus, bunyavirus, calicivirus, coronavirus, phyllovirus, hepadonavirus, herpesvirus, orthomixovirus, papovavirus, paramixovirus, parvovirus, picornavirus, etc. Poxvirus, Leovirus, Retrovirus, Rabdovirus, Togavirus, Papillomavirus (eg, Human Papillomavirus (HPV)), Human Immunodeficiency Virus (HIV), Poliovirus, Hepatitis Virus (eg, Hepatitis A Virus) (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), hepatitis E virus (HEV)), natural pox virus (eg, large pox, small sputum), Waxinia virus, influenza virus, rhinovirus, dengue fever virus, horse encephalitis virus, ruin virus, yellow fever virus, no walk virus, human T cell leukemia virus (HTLV-I), hairy cell leukemia virus (HTLV-II), California encephalitis Virus, hunter virus (hemorrhagic fever), mad dog disease virus, Ebola fever virus, Marburg virus, measles virus, epidemic parotitis virus, respiratory rash virus (RSV), simple herpes type 1 (oral herpes), simple herpes Type 2 (pudendal herpes), herpes zoster (varicella / herpes zoster virus), cytomegalovirus (CMV), Epstein-bar virus (EBV), flavivirus, mouth-foot epidemic virus, chikungunya virus, lassa virus, arenavirus or carcinogenic virus Infectious diseases caused by the virus.

Parasite infections include, for example, Onchocerciasis, Amoeba disease, Roundworm disease, Babesia disease, Valantedium disease, Pinworm roundworm disease, Shagas disease, Fasciolosis, Kokuriomiya, Cryptospolidiamosis, Diphyllobothriasis, Dracunculiasis. Insect disease, Echinococariasis, Elephant skin disease, Pinworm disease, Fasciolosis, Enlarged fasciolosis, Filasciolosis, Diphyllobothriasis, Jaw mouthworm disease, Membrane-like streak disease, Isosporosis, Katayama fever, Leishmania disease, Lime Diseases, malaria, Yokokawa worm disease, flyworm disease, onchocerciasis, sycamore parasites, scabies, blood-sucking worm disease, African sleep disease, fecal nematode disease, tenya streak disease, toxocariasis, toxoplasmosis, curly worm disease and whipworm Diseases and the like can be mentioned.

Bacterial infections include, for example, tuberculosis, charcoal, pathogenic bacteria, food poisoning, salmonella, staphylococcus, streptococcus, tetanus, mycobacteria, tetanus, pesto, methicillin-resistant yellow staphylococcus ( Examples include infectious diseases caused by infection with antibiotic-resistant bacteria such as MRSA) and Clostridium-difficile and other infectious bacteria.

Fungal infections include, for example, Aspergillus species, Blastomycosis dermatidis, Candida albicans (eg Candida albicans), Coccidioidomycosis, Cryptococcus neoformans, Cryptococcus gatti, Dermatophytes, Fuzarium species, Histoprasma. Infectious diseases caused by infections with Capslatum, Coccidioidomycosis, Pneumocystis girobesi, Sporortrix shenky, Exerohyram or Cryptococcus.

[Combination or combination drug]
The compound of the present invention or a pharmaceutical composition containing the compound of the present invention as an active ingredient (hereinafter, abbreviated as "the compound of the present invention") has (a) suppression of progression of cancer or infectious disease, suppression of recurrence and / or therapeutic effect. To enhance (b) to reduce the dose of other drugs prescribed in combination, (c) to reduce the side effects of other drugs prescribed in combination, and / or (d) ) In order to enhance the immunopotentiating effect of other drugs prescribed in combination, that is, as an adjuvant, it may be prescribed in combination with one or more other drugs. In the present invention, the administration form when prescribed in combination with other drugs may be a combination drug form in which both components are mixed in one preparation, or an administration form as separate preparations. Good. By the combined use, the preventive effect of other drugs, suppression of symptom progression, suppression of recurrence and / or therapeutic effect can be complemented, and the dose or frequency of administration can be maintained or reduced. When the compound of the present invention and other drugs are prescribed separately, they may be administered simultaneously for a certain period of time, and then only the compound of the present invention or other drugs may be administered. Further, the compound of the present invention or the like may be administered first, and then another drug may be administered, the other drug may be administered first, and the compound of the present invention or the like may be administered later. In the above administration, there may be a period during which both drugs are simultaneously administered for a certain period of time. Moreover, the administration method of each drug may be the same or different. Depending on the nature of the drug, it can also be provided as a kit of a preparation containing the compound of the present invention and a preparation containing another drug. Here, the dose of the other drug can be appropriately selected based on the clinically used dose. In addition, other drugs may be administered in combination of any two or more at an appropriate ratio. In addition, the other drugs include not only those found so far but also those found in the future.

Anticancer agents that can be used in combination with the compounds of the present invention in cancer treatment include, for example, alkylating agents (eg, dacarbazine, Nimustine, Temozolomide, Fotomustine, bendamustine, Cyclophosphamide, Ifosfamide, Carmustine, Chlorambucil and Procarbazine etc.), platinum preparations (eg Cisplatin, Carboplatin, Nedaplatin and oxaliplatin etc.), antimetabolites (eg folic acid antimetabolites (eg Pemetrexed, leucovorin and Methotrexate etc.), pyridine metabolism inhibitors (eg TS-1) ®, 5-fluorouracil, UFT, Carmofur, Doxifluridine, FdUrd, Cytarabine and Capecitabine, etc., purine metabolism inhibitors (eg, Fludarabine, Cladribine, Nelarabine, etc.), ribonucleotide reductase inhibitors, nucleotide analogs (eg, Gemcitabine) Etc.)), topoisomerase inhibitors (eg, Irinotecan, Nogitecan and Etoposide, etc.), microtube antimetabolites (eg, Vinblastine, Vincristine, Vindesine, Vinorelbine, Eribulin, etc.), microtubule depolymerization inhibitors (eg, Docetaxel and Paclitaxel) ), Anti-neoplastic antibiotics (eg, Bleomycin, Mitomycin C, Doxorubicin, Danourubicin, Idarbicin, Etoposide, Mitoxantrone, Vinblastine, Vincristine, Peplomycin, Amrubicin, Aclarubicin and Epirubicin, etc.), Cytological preparations (eg, IFN-α2a, IFN-α2a, IFN- α2b, peg IFN-α2b, natural IFN-β and Interleukin-2, etc.), anti-hormonal drugs (eg, Tamoxifen, Fulvestrant, Goserelin, Leuprorelin, Anastrozole, Letrozole, Exemestane, etc.), molecular target drugs, cancer exemption Examples include epidemic remedies and other antibody drugs.

Here, as the molecular target drug, for example, an ALK inhibitor (for example, Crizotinib, Ceritinib, Ensartinib, Alectinib and Lorlatinib), a BCR-ABL inhibitor (for example, Imatinib and Dasatinib), and an EGFR inhibitor (for example, Erlotinib, EGF816). , Afatinib, Osimertinib mesylate, Gefitinib and Rociletinib), B-Raf inhibitors (eg Sorafenib, Vemurafenib, TAK-580, Dabrafenib, Encorafenib, LXH254, Emurafenib and BGB-3111), VEGFR inhibitors (eg Bevacizumab, Apatinib, Lenvatinib, Aflibercept and Axitinib), FGFR inhibitors (eg AZD4547, B-701, FGF401 and INCB054828), c-Met inhibitors (eg Savolitinib, merestinib, Capmatinib, INC280 and Gresatinib), Axl inhibitors (eg , ONO-7475 and BGB324), Mek inhibitors (eg Cobimetinib, Binimetinib, Selumetinib and Trametinib), CDK inhibitors (eg Dinaciclib, Abemaciclib, Palbociclib and trilaciclib), Btk inhibitors (eg ONO-4059, Ibrutinib and Acalabrutinib), PI3K-δ / γ inhibitors (eg TGR-1202, INCB050465 and IPI-549), JAK-1 / 2 inhibitors (eg Itacitinib and Luxolitinib), ERK inhibitors (eg SCH 900353), TGFbR1 Inhibitors (eg Galunisertib), Cancer cell stemness kinase inhibitors (eg Amcasertib), FAK inhibitors (eg Defactinib), Syk / FLT3 dual inhibitors (eg TAK-659), ATR inhibitors (eg AZD6738) ), Wee1 kinase inhibitors (eg AZD1775), multityrosine kinase inhibitors (eg Sunitinib, Pazo) panib, Cabozantinib, Regorafenib, Nintedanib, Sitravatinib and Midostaurin), mTOR inhibitors (eg Temsirolimus, Everolimus, Vistusertib, Irinotecan), HDAC inhibitors (eg Vorinostat, Romidepsin, Entinostat, Chidamide, Mocetinostat) , PARP inhibitors (eg Niraparib, Olaparib, Veliparib, Rucaparib, Beigene-290), aromatase inhibitors (eg Exemestane, Letrozole), EZH2 inhibitors (eg tazemetostat), galectin-3 inhibitors (eg GR-) MD-02), STAT3 inhibitor (eg Napabucasin), DNMT inhibitor (eg Azacitidine), SMO inhibitor (eg Vismodegib), Hsp90 inhibitor (eg XL888), γ-tubulin specific inhibitor (eg XL888) For example, Glaziovianin A, Plinabulin), HIF2α inhibitor (eg PT2385), glutaminase inhibitor (eg CB-839), E3 ligase inhibitor (eg Avadomidide), Nrf2 activator (eg Omaveloxolone), arginase inhibitor Agents (eg, CB-1158), cell cycle inhibitors (eg, Trabectedin), Ephrin B4 inhibitors (eg, sEphB4-HAS), IAP antagonists (eg, Birinapant), anti-Her2 antibodies (eg, Trastuzumab, Trastuzumab emtansine) , Pertuzumab and Margetuximab), anti-EGFR antibodies (eg Cetuximab, Panitumumab, Necitumumab and Nimotuzumab) anti-VEGF antibodies (eg Bevacizumab), anti-VEGFR2 antibodies (eg Ramucirumab), anti-CD20 antibodies (eg Rituximab, Ofatumumab, Ulit Obinutuzumab), anti-CD30 antibody (eg, Brentuximab Vedotin) ), Anti-CD38 antibody (eg, Daratumumab), anti-DR5 antibody (eg, DS-8273a), anti-CA125 antibody (eg, Oregovomab), anti-DLL4 antibody (eg, Demcizumab), anti-fucosyl GM1 antibody (eg, BMS-986012) ), Anti-gpNMB antibody (eg Glembatumumab vedotin), anti-Mesothelin antibody (eg BMS-986148), anti-MMP9 antibody (eg Andecaliximab), anti-GD2 antibody (eg Dinutuximab-β), anti-c-Met antibody (eg BMS-986148) , ABT-399), anti-FOLR1 antibody (eg, Mirvetuximab soravtansine), anti-Ang2-VEGF bispecific antibody (eg, Vanucizumab), anti-CD30-CD16A bispecific antibody (eg, AFM13), anti-CD79b antibody (eg, AFM13) For example, Polatuzumab Vedotin), anti-FAP antibody / IL-2 fusion protein (eg RO6874281), anti-CEA antibody / IL-2 fusion protein (eg Cergutuzumab amunaleukin), anti-CEA-CD3 bispecific antibody (eg RO6958688). ), Anti-DLL3 antibody (eg, Rovalpituzumab tesirine), anti-CD3-CD19 bispecific antibody (eg, Blinatumomab) and anti-CD20-CD3 bispecific antibody (eg, REGN1979).

Examples of cancer immunotherapeutic agents include anti-PD-1 antibodies (eg, Nivolumab, Cemiplimab (REGN-2810), Pembrolizumab (MK-3475), Spartanizumab (PDR-001), Tislelizumab (BGB-A317), etc. AMP-514 (MEDI0680), Dostarlimab (ANB011 / TSR-042), Toripalimab (JS001), Camrelizumab (SHR-1210), Genolimzumab (CBT-501), Sintilimab (IBI308), STI-A1110, ENUM 388D4, ENUM 244C8, GLS010, MGA012, AGEN2034, CS1003, HLX10, BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, Sym021, GB226, SSI-361, JY034, HX008, ABBV181, BCD-100, PF-06801591, CX-188 , JNJ-63723283 and AB122, etc.), anti-PD-L1 antibody (eg Atezolizumab (RG7446 / MPDL3280A), Avelumab (PF-06834635 / MSB0010718C), Durvalumab (MEDI4736), BMS-936559, STI-1014, KN035, LY3300054, HLX20, SHR-1316, CS1001, MSB2311, BGB-A333, KL-A167, CK-301, AK106, AK104, ZKAB001, FAZ053, CBT-502, JS003 and CX-072, etc.), PD-1 antagonists (eg, AUNP-12, BMS-M1 to BMS-M10 compounds (WO2014 / 151634, WO2016 / 039749, WO2016 / 057624, WO2016 / 077518, WO2016 / 100285, WO2016 / 100608, WO2016 / 126646, WO2016 / 149351, WO2017 / 151830 And WO2017 / 176608), BMS-1, BMS-2, BMS-3, BMS-8, BMS-37, BMS-200, BMS-202, BMS-230, BMS-242, BMS-1001 and BMS-1166 (WO2015 / 034820, WO2015 / 1606 41, WO2017 / 066227 and Oncotarget. 2017 Sep 22; 8 (42): 72167-72181.), Incyte-1 to Incyte-6 compounds (WO2017 / 070089, WO2017 / 087777, WO2017 / 106634, WO2017 / 112730) , WO2017 / 192961 and WO2017 / 205464), CAMC-1 to CAMC-4 (see WO2017 / 202273, WO2017 / 202274, WO2017 / 202275 and WO2017 / 202276), RG_1 (see WO2017 / 118762) and DPPA-1 (Angew) . Chem. Int. Ed. 2015, 54, 11760-11764, etc.), PD-L1 / VISTA antagonists (eg, CA-170, etc.), PD-L1 / TIM3 antagonists (eg, CA-327, etc.) , Anti-PD-L2 antibody, PD-L1 fusion protein, PD-L2 fusion protein (eg, AMP-224, etc.), anti-CTLA-4 antibody (eg, Ipilimumab (MDX-010), AGEN1884 and Tremelimumab, etc.), anti-LAG -3 antibodies (eg Relatlimab (BMS-986016 / ONO-4482), LAG525, REGN3767 and MK-4280, etc.), LAG-3 fusion proteins (eg, IMP321, etc.), anti-Tim3 antibodies (eg, MBG453 and TSR-022, etc.) Etc.), anti-KIR antibody (eg Lirilumab (BMS-986015 / ONO-4483), IPH2101, LY3321367 and MK-4280 etc.), anti-BTLA antibody, anti-TIGIT antibody (eg Tiragolumab (MTIG-7192A / RG-6058 / etc.) RO-7092284) and BMS-986207 (ONO-4686 etc.), anti-VISTA antibody (eg JNJ-61610588 etc.), anti-CD137 antibody (eg Urrelumab (ONO-4481 / BMS-663513)) and Utomilumab (PF-05082566) Etc.), Anti-CSF-1R antibody / CSF-1R inhibitor (for example, Cabiralizumab (FPA008 / BMS-986227 / ONO-4687), Emactuzumab (RG7155 / RO5509554), LY3022855, MCS-110, I MC-CS4, AMG820, Pexidartinib, BLZ945 and ARRY-382 etc.), Anti-OX40 antibody (eg MEDI6469, PF-04518600, MEDI0562, MEDI6383, Efizonerimod, GSK3174998, BMS-986178 and MOXR0916 etc.), Anti-HVEM antibody, anti-CD27 Antibodies (eg, Varlilumab (CDX-1127), etc.), anti-GITR antibodies (eg, MK-4166, INCAGN01876, GWN323 and TRX-518, etc.), anti-CD28 antibodies, anti-CCR4 antibodies (eg, Mogamulizumab, etc.), anti-B7- H3 antibody (eg, Enoblituzumab, etc.), anti-ICOS agonist antibody (eg, JTX-2011 and GSK3359609, etc.), anti-CD4 antibody (eg, MTRX-1011A, TRX-1, Ibalizumab, huB-F5, Zanolimumab, 4162W94, Clenoliximab, Keliximab, AD-519, PRO-542, Cedelizumab, TNX-355, Dacetuzumab, Tregalizumab, Priliximab, MDX-CD4, CAMPATH-9 and IT1208, etc.), anti-DEC-205 antibody / NY-ESO-1 fusion protein (eg, CDX-1401 etc.), anti-SLAMF7 antibody (eg Ellotuzumab etc.), anti-CD73 antibody (eg Oleclumab and BMS-986179 etc.), anti-CD122 antibody (eg NKTR-214 etc.), anti-CD40 agonist antibody (eg ABBV) -428, APX005M and RO7009789, etc.), IDO inhibitors (eg, Epacadostat, Indoximod and BMS-986205, etc.), TLR agonists (eg, Motolimod, CMP-001, G100, IMO-2125, SD-101 and MEDI9197, etc.), Adenosine A2A receptor antagonists (eg Preladenant, AZD4635, PBF 509 and CPI-444 etc.), anti-NKG2A antibodies (eg Monalizumab etc.), anti-CSF-1 antibodies (eg PD0360324 etc.), immunopotentiators (eg PD0360324 etc.) PV-10 etc.), IL-15 super-antibody (eg ALT-803 etc.), soluble LAG3 (eg IMP321) Etc.), CD47 antagonists (eg, ALX148, etc.) and IL-12 antagonists (eg, M9241 etc.). Nivolumab can be manufactured according to the method described in WO2006 / 121168, Pembrolizumab can be manufactured according to the method described in WO2008 / 156712, and BMS-936559 can be manufactured according to WO2007 / 005874. Can be produced according to the method described in, and Ipilimumab can be produced according to the method described in WO2001 / 014424.

Furthermore, examples of other antibody drugs include anti-IL-1β antibodies (eg, Canakinumab, etc.) and anti-CCR2 antibodies (eg, Plozalizumab, etc.).

[Prescription]
In order to use the compound of the present invention or a combination drug of the compound of the present invention and another drug for the above purpose, it is usually administered systemically or topically, orally or parenterally. The dose varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually orally administered once to several times a day in the range of 1 ng to 2,000 mg per adult. Or orally administered once to several times daily in the range of 0.1 ng to 200 mg per adult, or given intravenously in the range of 30 minutes to 24 hours daily. Will be done. Of course, as described above, since the dose varies depending on various conditions, a dose smaller than the above dose may be sufficient, or administration beyond the range may be necessary.

[Formulation]
When administering the compound of the present invention or a concomitant drug of the compound of the present invention and another drug, a solid or liquid preparation for oral administration, a sustained-release preparation or a release-controlled preparation for oral administration, or an injection for parenteral administration. , Used as an infusion solution, external preparation, inhalant, suppository, etc.

Examples of solid preparations for oral administration include tablets, pills, capsules, powders and granules, and capsules include hard capsules and soft capsules.

The solid may be formulated, for example, with a pharmaceutically acceptable carrier of the compound of the invention. Here, examples of the pharmaceutically acceptable carrier used for formulating the solid preparation include excipients (for example, lactose, mannitol, glucose, microcrystalline cellulose and starch, etc.) and binders (for example, hydroxy). Hydroxycellulose, polyvinylpyrrolidone and magnesium aluminometasilicate, etc.), disintegrants (eg, calcium fibroglycolate, etc.), lubricants (eg, magnesium stearate, etc.), stabilizers, solubilizers (eg, glutamate, etc.) Aspartic acid, etc.) and the like. Further, if necessary, it may be coated with a coating agent (for example, sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc.), or may be coated with two or more layers. Furthermore, it may be included in a capsule containing gelatin.

The liquid preparation for oral administration may be in any form such as a liquid preparation, a suspension preparation, an emulsion, a syrup preparation and an elixir preparation, and for example, the compound of the present invention may be used as a diluent (for example, purified water, ethanol or). It may be dissolved, suspended or emulsified in a mixed solution thereof, etc. and formulated. Further, the liquid agent may contain a wetting agent, a suspending agent, an emulsifier, a sweetening agent, a flavoring agent, a fragrance agent, a preservative, a buffering agent and the like.

The sustained-release preparation for oral administration may contain, for example, a gel-forming substance, and the gel-forming substance includes, for example, gum arabic, canten, polyvinylpyrrolidone, sodium alginate, propylene glycol alginate, and carboxyvinyl polymer. , Carboxymethyl cellulose, sodium carboxymethyl cellulose, guagam, gelatin, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, methyl cellulose, hydroxyethyl methyl cellulose and the like.

Injections or infusions for parenteral administration may be in the form of aqueous solutions, suspensions or emulsions and at the time of use solvents (eg, distilled water for injection, saline, glucose solutions and By adding an isotonic solution (eg, a solution of sodium chloride, potassium chloride, glycerin, mannitol, sorbitol, boric acid, borosand, propylene glycol, etc.), it can be dissolved, suspended or emulsified before use. It may be formulated as a solid with a pharmaceutically acceptable carrier. Here, examples of the "pharmaceutically acceptable carrier" include stabilizers (for example, various amino acids, albumin, globulin, gelatin, mannitol, glucose, dextran, ethylene glycol, propylene glycol, polyethylene glycol, ascorbic acid, sulfite). Sodium hydrogen hydrogen, sodium thiosulfate, sodium edetate, sodium citrate and dibutylhydroxytoluene, etc.), solubilizers (eg, alcohol (eg, ethanol, etc.), polyalcohol (eg, propylene glycol, polyethylene glycol, etc.) and nonionic Sexual surfactants (eg, Polysorbate 20®, Polysolvate 80® and HCO-50, etc.), suspending agents (eg, glycerin monostearate, aluminum monostearate, methylcellulose, carboxymethylcellulose, etc.) , Hydroxymethyl cellulose and sodium lauryl sulfate, etc.), emulsifiers (eg, gum arabic, sodium alginate, tragant, etc.), soothing agents (eg, benzyl alcohol, chlorobutanol, sorbitol, etc.), buffers (eg, phosphate buffer, etc.) Acetate buffer, borate buffer, carbonate buffer, citrate buffer, tris buffer, glutamate buffer, epsilon aminocaproic acid buffer, etc.), preservatives (eg, methyl paraoxybenzoate, ethyl paraoxybenzoate, paraoxy) Propyl benzoate, butyl paraoxybenzoate, chlorobutanol, benzyl alcohol, benzalconium chloride, sodium dehydroacetate, sodium edetate, boric acid and boar sand, etc.), preservatives (eg, benzalconium chloride, paraoxybenzoic acid and Chlorobutanol, etc.), pH adjusters (eg, hydrochloric acid, sodium hydroxide, phosphoric acid, acetic acid, etc.), antioxidants, and the like. Antioxidants include, for example, (1) water-soluble antioxidants such as (1) ascorbic acid, cysteine hydrochloride, sodium bisulfite, sodium metabisulfite and sodium bisulfite, (2) ascorbic palmitate, butylated hydroxyanisol, etc. Use oil-soluble antioxidants such as butylated hydroxytoluene, lecithin, propyl gallate and α-tocopherol and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid, sorbitol, tartaric acid and phosphoric acid. Can be done.

The injection or infusion solution can be produced by sterilization in the final step or by aseptic technique, for example, filtering through a filter or the like to sterilize, and then filling in a sterile container. In addition, the injection or infusion solution can also be used by dissolving aseptic powder (which may contain pharmaceutically acceptable carrier powder) by vacuum drying and lyophilization in a suitable solvent before use. ..

Dosage forms of external preparations for parenteral administration include, for example, sprays, inhalants, sprays, aerosols, ointments, gels, creams, poultices, patches, liniments and nasal drops. Can be mentioned.

In addition to commonly used diluents, the sprays, inhalants and sprays are buffers that provide isotonicity with stabilizers such as sodium bisulfite, such as sodium chloride, sodium citrate or citric acid. It may contain an isotonic agent such as. The method for producing the spray agent is described in detail in, for example, US Pat. No. 2,868,691 and No. 3095355.

Examples of the inhalant include an inhalation solution or an inhalation powder, and the solution may be used by being dissolved or suspended in water or another suitable medium at the time of use. These inhalants are manufactured according to known methods, for example, in the case of inhalation liquids, preservatives (eg, benzalkonium chloride and parabens, etc.), colorants, buffers (eg, sodium acetate, etc.). And sodium acetate, etc.), isotonic agents (eg, sodium chloride and concentrated glycerin, etc.), thickeners (eg, carboxyvinyl polymers, etc.), absorption enhancers, etc., which are appropriately mixed as necessary, while being prepared. , Preservatives (eg, stearic acid and salts thereof), binders (eg, starch and dextrin, etc.), excipients (eg, lactose and cellulose, etc.), colorants, in the case of inhalable powders, It is prepared by appropriately mixing preservatives (for example, benzalkonium chloride, paraben, etc.) and absorption enhancers, if necessary. When administering an inhalation solution, a sprayer (for example, an atomizer and a nebulizer) is usually used, while when administering an inhalation powder, an inhalation dispenser for powdered drug is usually used.

The ointment is prepared according to a known or commonly used formulation, for example, the compound of the present invention is mixed or melted in an ointment base. Here, the ointment base is selected from known or commonly used ones, for example, higher fatty acids or higher fatty acid esters (eg, adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, etc. Myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester, etc.), waxes (eg, beeswax, whale wax, ceresin, etc.), surfactants (eg, polyoxyethylene alkyl ether phosphate, etc.), higher grade Alcohols (eg, cetanol, esteryl alcohols and cetostearyl alcohols, etc.), silicon oils (eg, dimethylpolysiloxane, etc.), hydrocarbons (eg, hydrophilic vaseline, white vaseline, purified lanolin and liquid paraffin, etc.), glycols (eg, eg , Ester glycol, diethylene glycol, propylene glycol, polyethylene glycol and macrogol, etc.), vegetable oil (eg, castor oil, olive oil, sesame oil and terepine oil, etc.), animal oil (eg, mink oil, egg yolk oil, squalane and squalane, etc.), water , One or more selected from an absorption promoter or an anti-rash agent are mixed and used. Further, it may contain a moisturizer, a preservative, a stabilizer, an antioxidant, a flavoring agent and the like.

Gels are prepared according to known or commonly used formulations, for example by melting the compounds of the invention into a gel base. Here, the gel base is selected from known or commonly used ones, for example, lower alcohols (eg ethanol and isopropyl alcohol), gelling agents (eg carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and the like. Selected from ethyl cellulose, etc.), neutralizers (eg, triethanolamine, diisopropanolamine, etc.), surfactants (eg, polyethylene glycol monostearate, etc.), gums, water, absorption enhancers, and anti-rash agents. It is used by mixing seeds and above. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.

Cream preparations are prepared according to known or commonly used formulations, and are produced, for example, by melting or emulsifying a compound of the present invention in a cream base. Here, the cream base is selected from known or commonly used ones, for example, higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (eg, propylene glycol and 1,3-butylene glycol, etc.). , Higher alcohols (eg 2-hexyldecanol and cetanol, etc.), emulsifiers (eg, polyoxyethylene alkyl ethers and fatty acid esters, etc.), water, absorption enhancers and anti-rash agents. Used. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.

The poultice is prepared by a known or commonly used formulation, for example, the compound of the present invention is melted in a poultice base, made into a kneaded product, and spread and applied on a support. Here, the wet cloth base is selected from those known or commonly used, for example, a thickener (for example, polyacrylic acid, polyvinylpyrrolidone, arabic rubber, starch, gelatin, methyl cellulose, etc.), a wetting agent (for example,). , Urea, glycerin and propylene glycol, etc.), fillers (eg, kaolin, zinc oxide, talc, calcium and magnesium, etc.), water, solubilizers, tackifiers and anti-rash agents. Is used. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.

The patch is prepared according to a known or commonly used formulation, for example, the compound of the present invention is melted in a base for a patch and spread on a support to prepare the patch. Here, the base for the patch is selected from known or commonly used ones, and for example, one or more selected from polymer bases, fats and oils, higher fatty acids, tackifiers and anti-rash agents are mixed. Is used. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.

Liniment agents are prepared according to known or commonly used formulations, for example, the compounds of the present invention are mixed with water, alcohols (eg ethanol and polyethylene glycol, etc.), higher fatty acids, glycerin, soap, emulsifiers and suspending agents, etc. It is prepared by dissolving, suspending or emulsifying in one or more selected from the above. Further, it may contain a preservative, an antioxidant, a flavoring agent and the like.

All patent documents and non-patent documents or references cited herein are all hereby incorporated herein by reference.

The present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited thereto. Various modifications or modifications are possible to those skilled in the art based on the description of the present invention, and these modifications or modifications are also included in the present invention.

[Example]
The description of Hi-flash SI or Hi-flash NH in parentheses shown in the section of medium pressure preparative liquid chromatography is the type of column used (Hi-flash SI: silica gel (manufactured by Yamazen Corporation), Hi-flash NH: Represents aminopropyl group-supported silica gel (manufactured by Yamazen Corporation).

LC-MS / ELSD was performed under the following conditions.
[Column: YMC Triart C18 (particle size: 1.9 x 10 ^-6 m; column length: 30 x 2.0 mm ID); flow velocity: 1.0 mL / min; column temperature: 40 ° C.; mobile phase (A): 0.1 % Trifluoroacetic acid aqueous solution; mobile phase (B): 0.1% trifluoroacetic acid-acetoform solution; gradient (state the ratio of mobile phase (A): mobile phase (B)): [0 min] 95: 5; [0.1 min] 95: 5; [1.2 min] 5:95; [1.4 min] 5:95; [1.41 min] 95: 5; [1.5 min] 95: 5; And detectors: UV (PDA), ELSD, MS]
The numerical value shown in the place of NMR is the measured value (chemical shift value) of ¹ H-NMR when the measuring solvent described in parentheses is used.

The compound names used in the present specification are computer programs generally named according to the IUPAC rules, ACD / Name (registered trademark) (version 6.00, manufactured by Advanced Chemistry Development Inc.), Chemdraw Ultra (version). 12.0, manufactured by Cambridge Soft, or Lexichem Toolkit (version 1.4.2, manufactured by OpenEye Scientific Software), or named according to the IUPAC nomenclature.

Reference Example 1: Lithium 2-chloro-4-fluoro-5-iodonicotinate

2-Chloro-4-fluoro-5-iodopyridine (CAS No. 1370534-60-3) (13.4 g) is dissolved in tetrahydrofuran (hereinafter abbreviated as THF) (50 mL) and cooled to −78 ° C. Then, lithium diisopropylamide (1 mol / L THF solution, 50 mL) was added dropwise over 30 minutes. After stirring at −78 ° C. for 1.5 hours, finely crushed dry ice (11.4 g) was added, and the mixture was stirred at −78 ° C. for 30 minutes. The reaction solution was heated to room temperature, and the obtained precipitate was collected by filtration to give the title compound (16.5 g) having the following physical characteristics.
LCMS retention time (minutes): 0.63;
MS (ESI, Pos.): 302 (M + H) ⁺ ;
^{1 1} H-NMR (DMSO-d ₆ ): δ 8.44 (d, J = 9.0Hz, 1H).

Reference Example 2: 2-Chloro-4-fluoro-5-iodonicotinonitrile

A mixture of the compound (16.0 g) prepared in Reference Example 1 and N, N-dimethylformamide (hereinafter abbreviated as DMF) (0.20 mL) and thionyl chloride (38.0 mL) was 3.5 at 80 ° C. Stirred for hours. The reaction mixture was concentrated, the solution of the obtained residue in THF (100 mL) was cooled to 0 ° C., and saturated aqueous ammonia (28%, 10.8 mL) was added dropwise with stirring. After stirring for 30 minutes, city water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The obtained residue was used in the next step without purification.

The crude product obtained by the above operation was dissolved in THF (174 mL), pyridine (21.1 mL) and trifluoroacetic anhydride (10.9 mL) were added under ice-cooling, and the mixture was stirred at 0 ° C. for 1 hour. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (Hi-flash SI) (hexane: ethyl acetate = 0: 100 to 70:30) to give the title compound (5.82 g) having the following physical characteristics.
LCMS retention time (minutes): 0.92;
MS (ESI, Pos.): 283 (M + H) ⁺ ;
^{1 1} H-NMR (CDCl ₃ ): δ 8.83 (d, J = 7.7Hz, 1H).

Reference Example 3: 2-Chloro-5-iodo-4-((propan-2-iridenamino) oxy) nicotinonitrile

Sodium-tert-butoxide (9.02 g) was added to a solution of propan-2-one oxime (6.86 g) in THF (100 mL) at room temperature, and the mixture was stirred for 1 hour (hereinafter, this solution is referred to as an oxime solution). .. The oxime solution was added dropwise to a solution of the compound (26.5 g) prepared in Reference Example 2 in THF (90 mL) under ice-cooling over 15 minutes. The reaction solution was heated to room temperature and then stirred for another 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Hi-flash SI) (hexane: ethyl acetate = 70:30) to give the title compound (31.1 g) having the following physical characteristics.
LCMS retention time (minutes): 1.02;
^{1 1} H-NMR (CDCl ₃ ): δ 8.67 (s, 1H), 2.21 (s, 3H), 2.13 (s, 3H).

Reference Example 4: 4-Chloro-7-iodoisoxazolo [4,5-c] Pyridine-3-amine

5 mol / L hydrochloric acid (70 mL) was added to an ethanol (70 mL) solution of the compound (4.66 g) prepared in Reference Example 3, and the mixture was stirred at 70 ° C. for 1 hour. The solid produced after the reaction was collected by filtration to give the title compound (2.93 g) having the following physical characteristics.
LCMS retention time (minutes): 0.76;
MS (ESI, Pos.): 296 (M + H) ⁺ ;
^{1 1} H-NMR (DMSO-d ₆ ): δ 8.65 (s, 1H), 6.59 (s, 2H).

Reference Example 5: 4-Bromo-7-iodoisoxazolo [4,5-c] Pyridine-3-amine

Bromethyltrimethylsilane (14.9 mL) was added to a propionitrile (55.5 mL) solution of the compound (5.55 g) prepared in Reference Example 4 at room temperature, and the solution was stirred at 105 ° C. for 3 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. A mixed solvent of hexane-ethyl acetate (4: 1,50 mL) was added to the residue, and the mixture was stirred for 30 minutes. The precipitate was collected by filtration to give the title compound (4.78 g) having the following physical characteristics.
LCMS retention time (minutes): 0.81;
MS (ESI, Pos.): 340 (M + H) ⁺ ;
^{1 1} H-NMR (CDCl ₃ ): δ 8.64 (s, 1H), 6.48 (s, 2H).

Reference Example 6: 4-Bromo-7- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine

In a nitrogen atmosphere, 1- (tetrahydro-2H-pyran-2-yl) -4- (4,4,5) was added to a solution of the compound (2.01 g) prepared in Reference Example 5 in 1,4-dioxane (25 mL). , 5-Tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (1.73 g) (CAS No.1003846-21-6), [1,1'-bis (diphenylphosphino) Ferrocene] Pyrazole (II) dioxane (484 mg) and a 2 mol / L tripotassium phosphate aqueous solution (5.9 mL) were added, and the mixture was stirred at 90 ° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and the insoluble material was filtered through a short silica gel pad. Water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. Methanol (10 mL) was added to the residue, and the mixture was stirred for 30 minutes. The precipitate was collected by filtration to give the title compound (1.50 g) having the following physical characteristics.
LCMS retention time (minutes): 0.80;
MS (ESI, Pos.): 364 (M + H) ⁺ ;

Reference Example 7: (5-Bromo-4-fluoro-2-nitrophenyl) (methyl) sulfan

(1-Bromo-2,5-fluoro-2-nitrophenyl) (methyl) sulfan (CAS No. 167415-27-2) (2.00 g) was dissolved in DMF (20 mL) and cooled to 0 ° C. An aqueous solution (4.2 mL) of sodium thiomethoxyde (707 mg) was added dropwise thereto, and the mixture was stirred under ice-cooling for 1.5 hours. The resulting precipitate was collected by filtration and dried to give the title compound (1.17 g) having the following physical characteristics.
LCMS retention time (minutes): 1.05;
^{1 1} H-NMR (CDCl ₃ ): δ 8.06 (d, J = 8.0Hz, 1H), 7.52 (d, J = 6.0Hz, 1H), 2.52 (s, 3H).

Reference Example 8: 4-Bromo-5-fluoro-2- (methylthio) aniline

Iron powder (1.23 g) was added to a solution of the compound (1.17 g) prepared in Reference Example 7 in acetic acid (12 mL), and the mixture was stirred at 90 ° C. for 1 hour. The reaction mixture was cooled to room temperature, filtered through Celite (registered trademark), and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Hi-flash NH) (hexane: ethyl acetate = 90: 10 to 70:30) to give the title compound (1.06 g) having the following physical characteristics.
LCMS retention time (minutes): 1.01;
MS (ESI, Pos.): 236 (M + H) ⁺ .
^{1 1} H-NMR (CDCl ₃ ): δ 7.52 (d, J = 7.5Hz, 1H), 6.50 (d, J = 10.5Hz, 1H), 4.45 (brs, 2H), 2.31 (s, 3H).

Reference Example 9: 4-Bromo-5-Fluoro-2- (Methylsulfonyl) Aniline

Metachloroperbenzoic acid (about 30% water content) (1.41 g) was added to a dichloromethane solution (8.0 mL) of the compound (500 mg) prepared in Reference Example 8 under ice-cooling. After stirring under ice-cooling for 1 hour, a 10% aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution were added, and the reaction was stopped. The solution was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Hi-flash SI) (hexane: ethyl acetate = 90: 10-50: 50) to give the title compound (487 mg) having the following physical characteristics.
LCMS retention time (minutes): 0.82;
MS (ESI, Pos.): 268 (M + H) ⁺ .

Reference Example 10: 1- (2-amino-5-bromo-4-fluorophenyl) ethane-1-one

4-Bromo-5-fluoro-2-iodoaniline (CAS No.1219741-79-3) (810 mg), copper (I) iodide (48.8 mg), tributyl (1-ethoxyvinyl) tin under a nitrogen atmosphere. (1.04 mL) and acetonitrile (10 mL) were mixed and degassed. Bis (triphenylphosphine) palladium (II) dichloride (180 mg) was added to the mixture, and the mixture was stirred at 80 ° C. for 5 hours. The reaction mixture was directly purified by silica gel column chromatography (Hi-flash SI) (hexane: ethyl acetate = 100: 0 to 70:30) to give the title compound (547 mg) having the following physical characteristics.
LCMS retention time (minutes): 0.91;
MS (ESI, Pos.): 232 (M + H) ⁺ .

Reference Example 11: 2-amino-5-bromo-N-ethyl-4-fluorobenzamide

2-Amino-5-bromo-4-fluorobenzoic acid (CAS No.143945-65-7) (2.20 g), 1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [ 4,5-b] A mixture of pyridinium 3-oxide hexafluorophosphate (HATU: CAS No. 148893-10-1) (4.60 g), N, N-diisopropylethylamine (2.4 mL) and DMF (47 mL). Was stirred at room temperature for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Hi-flash SI) (hexane: ethyl acetate = 90: 10-60: 40) to give the title compound (2.08 g) having the following physical characteristics.
LCMS retention time (minutes): 0.84;
MS (ESI, Pos.): 261 (M + H) ⁺ .

Reference Example 12: 5-Fluoro-2- (methylsulfonyl) -4- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline

Under a nitrogen atmosphere, 1,4-dioxane (8.0 mL) was added to a mixture of the compound (487 mg), bis (pinacolato) diboron (922 mg) and potassium acetate (713 mg) prepared in Reference Example 9 to perform a degassing operation. went. [1,1'-Bis (diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex (148 mg) was added thereto, and the mixture was stirred at 90 ° C. overnight. The reaction mixture was filtered through Celite® and the filtrate was concentrated. The residue was purified by silica gel column chromatography (Hi-flash SI) (hexane: ethyl acetate = 100: 0 to 80:20) to give the title compound (342 mg) having the following physical characteristics.
LCMS retention time (minutes): 0.91;
MS (ESI, Pos.): 316 (M + H) ⁺ .

Reference Examples 12 (1) to 12 (5)
Using a bromoaryl compound corresponding to 4-bromo-5-fluoro-2- (methylsulfonyl) aniline of Reference Example 9 and performing the same operation as in Reference Example 12, a title compound having the following physical property values was obtained. It was.

Reference Example 12 (1): Methyl 2-amino-4-fluoro-5- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate

LCMS retention time (minutes): 1.04;
MS (ESI, Pos.): 296 (M + H) ⁺ .

Reference Example 12 (2): 5-Fluoro-2- (methylthio) -4- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) aniline

LCMS retention time (minutes): 1.06;
MS (ESI, Pos.): 284 (M + H) ⁺ .

Reference Example 12 (3): 1- (2-amino-4-fluoro-5- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) phenyl) ethane-1- on

LCMS retention time (minutes): 0.99;
MS (ESI, Pos.): 280 (M + H) ⁺ .

Reference Example 12 (4): 2-amino-N-ethyl-4-fluoro-5- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide

LCMS retention time (minutes): 0.91;
MS (ESI, Pos.): 309 (M + H) ⁺ .

Reference Example 12 (5): 2-amino-4-chloro-N-ethyl-5- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide

LCMS retention time (minutes): 1.14;
MS (ESI, Pos.): 325 (M + H) ⁺ .

Reference Example 13: Methyl 2-amino-5- (3-amino-7- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridine -4-yl) -4-fluorobenzoate

In a nitrogen atmosphere, in a DMF (1.37 mL) solution of the compound (100 mg) prepared in Reference Example 6, the boronic acid ester (89.1 mg) prepared in Reference Example 12 (1) and bis [di-tert-butyl (di-tert-butyl). 4-Dimethylaminophenyl) phosphine] palladium (19.4 mg) and a 2 mol / L sodium carbonate aqueous solution (0.27 mL) were added, and the mixture was stirred at 110 ° C. for 2 hours. After cooling to room temperature, city water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Hi-flash SI) (hexane: ethyl acetate = 95: 5-20: 80) to give the title compound (110 mg) having the following physical properties.
LCMS retention time (minutes): 0.75;
MS (ESI, Pos.): 453 (M + H) ⁺ .

Example 1: Methyl 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorobenzoate

Trifluoroacetic acid (4.0 mL) was added to a solution of the compound (388 mg) prepared in Reference Example 13 in dichloromethane (4.0 mL), and the mixture was stirred at 40 ° C. for 5 hours. Saturated sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Hi-flash SI) (hexane: ethyl acetate = 90: 10-0: 100) to obtain the compound of the present invention (19.6 mg) having the following physical properties.
LCMS retention time (minutes): 0.59;
MS (ESI, Pos.): 369 (M + H) ⁺ ;
^{1 1} H-NMR (CD ₃ OD): δ 8.86 (s, 1H), 8.34 (s, 2H), 8.05 (d, J = 8.5Hz, 1H), 6.66 (d, J = 12.5Hz, 1H), 3 , 85 (s, 3H).

Example 2: 4- (4-Amino-2-fluoro-5-methoxyphenyl) -7- (1H-pyrazol-4-yl) isoxazolo [4,5-c] Pyridine-3-amine Hydrochloride Under nitrogen atmosphere , 5-Fluoro-2-methoxy-4- (4,5,5-tetramethyl-1,3) in a 1,4-dioxane (7.1 mL) solution of the compound (235 mg) prepared in Reference Example 6. , 2-Dioxaborolan-2-yl) aniline (CAS No. 1326283-60-6) (224 mg), bis [tri-tert-butylphosphine] palladium (65.9 mg), and 2 mol / L tripotassium phosphate aqueous solution (2 mol / L tripotassium phosphate solution 1.1 mL) was added, and the mixture was stirred at 110 ° C. for 3 hours. The reaction mixture was directly purified by silica gel column chromatography (Hi-flash SI) (hexane: ethyl acetate = 100: 0-0: 100) and 4- (4-amino-2-fluoro-5-methoxyphenyl) -7. -(1- (Tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) isoxazolo [4,5-c] pyridine-3-amine (108 mg) was obtained.

Hydrochloric acid (10% methanol solution, 2.0 mL) was added to a solution of this compound (108 mg) in THF (2.2 mL), and the mixture was stirred at room temperature for 2 hours. Saturated sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate-methanol (9: 1). The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Hi-flash SI) (ethyl acetate: methanol = 100: 0 to 90:10). After concentration, the residue was dissolved in methanol (5.0 mL), hydrochloric acid (10% methanol solution, 0.8 mL) was added, and the mixture was concentrated. Ethyl acetate (50 mL) was added to the residue, and the mixture was stirred under heating under reflux for 1 hour. The mixture was concentrated to obtain the compound of the present invention (87 mg) having the following physical characteristics.
LCMS retention time (minutes): 0.54;
MS (ESI, Pos.): 341 (M + H) ⁺ ;
^{1 1} H-NMR (CD ₃ OD): δ 8.96 (s, 1H), 8.44 (s, 2H), 7.11 (d, J = 6.5Hz, 1H), 6.70 (d, J = 12.0Hz, 1H), 3.93 (s, 3H).

Example 3: 1- (2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorophenyl) ethane In a -1-one nitrogen atmosphere, the compound (10.0 g) prepared in Reference Example 6 was added to a solution of 1-methyl-2-pyrrolidone (hereinafter abbreviated as NMP) (100 mL) in Reference Example 12 (3). The prepared boronate ester (10.7 g), butyldi-1-adamantylphosphine (984 mg), palladium acetate (308 mg), potassium iodide (456 mg) and 2 mol / L tripotassium phosphate aqueous solution (28 mL) were added, and 50 to 50 to The mixture was stirred at 60 ° C. for 45 hours. After allowing the reaction solution to cool, the insoluble material was removed by filtration while washing with NMP. City water (240 mL) was added little by little to the filtrate and stirred for 40 minutes, and the precipitated solid was collected by filtration. The solid was slurry-washed with acetonitrile (80 mL, 2 times) and methyl tert-butyl ether (80 mL, 2 times), collected by filtration, and dried to obtain 1- (2-amino-5- (3-amino-7-). (1- (Tetrahydro-2H-pyran-2-yl) -1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorophenyl) ethane-1-one (8) .52 g) was obtained.

Methanol (24 mL) and methanesulfonic acid (3.96 g) were added to this compound (6.00 g), and the mixture was stirred at 55 ° C. for 3 hours. The reaction mixture was allowed to cool to room temperature, triethylamine (18 mL) was added, and the mixture was stirred at 55 ° C. for 2.5 hours. After allowing to cool, the resulting precipitate was filtered to give a beige powder. Methanol (40 mL) was added to this powder, the slurry was washed at room temperature, filtered and dried to obtain the compound of the present invention (4.50 g) having the following physical properties.
LCMS retention time (minutes): 0.56;
MS (ESI, Pos.): 353 (M + H) ⁺ ;
¹ H-NMR (DMSO-d ₆ ): δ 13.3 (s, 1H), 8.97 (s, 1H), 8.47 (s, 1H), 8.23 (s, 1H), 7.98 (d, J = 8.5Hz, 1H) ), 7.71 (brs, 2H), 6.67 (d, J = 13.0Hz, 1H), 5.73 (s, 2H), 2.52 (s, 3H).

Example 4: 4- (4-Amino-2-fluoro-5- (methylthio) phenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] Pyridine-3-amine hydrochloride Reference Reference Example 12 instead of the methyl 2-amino-4-fluoro-5- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzoate produced in Example 12 (1). 4- (4-Amino-2-fluoro-5- (methylthio) phenyl) -7- (1) obtained by performing the same operation as in Reference Example 13 using the boronic acid ester produced in (2). -(Tetrahydro-2H-pyran-2-yl) -1H-pyrazole-4-yl) isoxazolo [4,5-c] Pyridine-3-amine (76.6 mg) in THF solution (1.5 mL) at room temperature Below, hydrochloric acid (10% methanol solution, 1.1 mL) was added, and the mixture was stirred for 1 hour. After the reaction, the resulting precipitate was collected by filtration to obtain the compound of the present invention (76.1 mg) having the following physical characteristics.
LCMS retention time (minutes): 0.60;
MS (ESI, Pos.): 357 (M + H) ⁺ ;
^{1 1} H-NMR (CD ₃ OD): δ 9.05 (s, 1H), 8.53 (s, 2H), 7.76 (d, J = 8.0Hz, 1H), 6.78 (d, J = 13.0Hz, 1H), 2.41 (s, 3H).

Examples 4 (1) to 4 (16)
4- (4-Amino-2-fluoro-5- (methylthio) phenyl) -7- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole-4-yl) isoxazolo [4,5- c] A compound corresponding to the substitute for pyridine-3-amine is produced by the same operation as described in Example 4, and then subjected to the same operation as described in Example 4 to have the following physical property values. The invention compound was obtained.

Example 4 (1): 4- (4-amino-3-methoxyphenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine hydrochloride
LCMS retention time (minutes): 0.51;
MS (ESI, Pos.): 323 (M + H) ⁺ ;
^{1 1} H-NMR (CD ₃ OD): δ 8.99 (s, 1H), 8.49 (s, 2H), 7.52 (s, 1H), 7.42 (d, J = 7.0Hz, 1H), 7.30 (d, J = 8.5Hz, 1H), 4.05 (s, 3H).

Example 4 (2): 4- (4-Amino-2-fluoro-5- (methoxy-d ₃ ) phenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridine- 3-Amine Hydrochloride
LCMS retention time (minutes): 0.55;
MS (ESI, Pos.): 344 (M + H) ⁺ ;
^{1 1} H-NMR (CD ₃ OD): δ 9.09 (s, 1H), 8.56 (s, 2H), 7.29 (d, J = 5.5, 1H), 6.95 (d, J = 9.0Hz, 1H).

Example 4 (3): 4- (4-Amino-2-fluoro-5- (methylsulfonyl) phenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] Pyridine-3-3 Amine hydrochloride
LCMS retention time (minutes): 0.55;
MS (ESI, Pos.): 389 (M + H) ⁺ ;
^{1 1} H-NMR (CD ₃ OD): δ 9.10 (s, 1H), 8.50 (s, 2H), 8.12 (d, J = 8.0, 1H), 6.90 (d, J = 12.5Hz, 1H), 3.17 ( s, 3H).

Example 4 (4): 4- (4-Amino-2-fluoro-3-methoxyphenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine hydrochloride
HPLC retention time (minutes): 0.55;
MS (ESI, Pos.): 341 (M + H) ⁺ ;
^{1 1} H-NMR (CD ₃ OD): δ 9.04 (s, 1H), 8.49 (s, 2H), 7.24 (dd, J = 8.5, 7.5, 1H), 6.84 (d, J = 8.5Hz, 1H), 3.99 (s, 3H).

Example 4 (5): 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorobenzamide hydrochloride
LCMS retention time (minutes): 0.50;
MS (ESI, Pos.): 354 (M + H) ⁺ ;
¹ H-NMR (DMSO-d ₆ ): δ 9.03 (s, 1H), 8.40 (s, 2H), 7.92 (d, J = 9.0, 1H), 7.79 (br s, 1H), 7.23 (br s, 1H), 6.64 (d, J = 12.0Hz, 1H), 5.98 (br s, 2H).

Example 4 (6): Ethyl 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorobenzoate hydrochloride salt
LCMS retention time (minutes): 0.69;
MS (ESI, Pos.): 383 (M + H) ⁺ ;
¹ H-NMR (DMSO-d ₆ ): δ 9.01 (s, 1H), 8.38 (s, 2H), 7.99 (d, J = 8.5, 1H), 7.30 (br s, 1H), 6.72 (d, J) = 13.0Hz, 1H), 5.83 (br s, 2H), 4.28 (q, J = 7.0Hz, 2H), 1.29 (t, J = 7.0Hz, 3H).

Example 4 (7): 1- (2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluoro Phenyl) Propane-1-one Hydrochloride
LCMS retention time (minutes): 0.77;
MS (ESI, Pos.): 367 (M + H) ⁺ ;
^{1 1} H-NMR (CD ₃ OD): δ 8.94 (s, 1H), 8.38 (s, 2H), 8.20 (d, J = 8.5Hz, 1H), 6.66 (d, J = 13.0Hz, 1H), 2.94 (q, J = 7.0Hz, 2H), 1.09 (t, J = 7.0Hz, 3H).

Example 4 (8): 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -N-ethyl-4-yl Fluorobenzamide hydrochloride
LCMS retention time (minutes): 0.70;
MS (ESI, Pos.): 382 (M + H) ⁺ ;
^{1 1} H-NMR (CD ₃ OD): δ 8.98 (s, 1H), 8.41 (s, 2H), 7.85 (d, J = 8.0Hz, 1H), 6.65 (d, J = 13.0Hz, 1H), 3.29 (q, J = 7.0Hz, 2H), 1.11 (t, J = 7.0Hz, 3H).

Example 4 (9): 1- (2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) phenyl) ethane- 1-on hydrochloride
LCMS retention time (minutes): 0.67;
MS (ESI, Pos.): 335 (M + H) ⁺ ;
^{1 1} H-NMR (CD ₃ OD): δ 8.86 (s, 1H), 8.37 (s, 2H), 8.29 (d, J = 2.0Hz, 1H), 7.64 (dd, J = 9.0, 2.0Hz, 1H) , 6.95 (d, J = 9.0Hz, 1H), 2.56 (s, 3H).

Example 4 (10): Methyl 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) benzoate hydrochloride
LCMS retention time (minutes): 0.71;
MS (ESI, Pos.): 351 (M + H) ⁺ ;
¹ H-NMR (DMSO-d ₆ ): δ 9.00 (s, 1H), 8.45 (s, 2H), 8.21 (s, 1H), 7.71 (d, J = 9.0Hz, 1H), 7.01 (d, J) = 9.0Hz, 1H), 6.02 (br s, 2H), 3.84 (s, 3H).

Example 4 (11): 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -N-propylbenzamide hydrochloride
LCMS retention time (minutes): 0.70;
MS (ESI, Pos.): 378 (M + H) ⁺ ;
^{1 1} H-NMR (CD ₃ OD): δ 8.86 (s, 1H), 8.38 (s, 2H), 7.95 (d, J = 2.0Hz, 1H), 7.60 (dd, J = 8.5, 2.0Hz, 1H) , 6.94 (d, J = 8.5Hz, 1H), 3.26-3.13 (m, 2H), 1.54 (q, J = 7.0Hz, 2H), 0.90 (t, J = 7.0Hz, 3H).

Example 4 (12): 1- (2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluoro Phenyl) butane-1-one hydrochloride
LCMS retention time (minutes): 0.90;
MS (ESI, Pos.): 381 (M + H) ⁺ ;
^{1 1} H-NMR (CD ₃ OD): δ 8.94 (s, 1H), 8.37 (s, 2H), 8.20 (d, J = 8.0Hz, 1H), 6.65 (d, J = 13.0Hz, 1H), 2.88 (t, J = 7.0Hz, 2H), 1.65 (q, J = 7.5Hz, 2H), 0.90 (t, J = 7.5Hz, 3H).

Example 4 (13): 1- (2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) phenyl) butane- 1-on hydrochloride
LCMS retention time (minutes): 0.87;
MS (ESI, Pos.): 363 (M + H) ⁺ ;
^{1 1} H-NMR (CD ₃ OD): δ 8.86 (s, 1H), 8.38 (s, 2H), 8.33 (d, J = 2.0Hz, 1H), 7.63 (dd, J = 9.0, 2.0Hz, 1H) , 6.96 (d, J = 9.0Hz, 1H), 2.96 (t, J = 7.5Hz, 2H), 1.70-1.64 (m, 2H), 0.92 (t, J = 7.0Hz, 3H).

Example 4 (14): 2-Hydroxyethyl 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4- Fluorobenzoate hydrochloride
LCMS retention time (minutes): 0.76;
MS (ESI, Pos.): 399 (M + H) ⁺ ;
^{1 1} H-NMR (CD ₃ OD): δ 8.97 (s, 1H), 8.39 (s, 2H), 8.30 (d, J = 8.5 Hz, 1H), 6.69 (d, J = 13.0 Hz, 1H), 4.26 (t, J = 5.0 Hz, 2H), 3.74 (t, J = 5.0 Hz, 2H).

Example 4 (15): 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -N-methylbenzamide hydrochloride
LCMS retention time (minutes): 0.69;
MS (ESI, Pos.): 350 (M + H) ⁺ ;
^{1 1} H-NMR (DMSO-d ₆ ): δ 9.04 (s, 1H), 8.56 (d, J = 4.5 Hz, 1H), 8.52 (s, 2H), 8.18 (d, J = 2.0Hz, 1H), 7.64 (dd, J = 8.5, 2.0Hz, 1H), 6.94 (d, J = 8.5Hz, 1H), 6.22 (s, 2H), 2.78 (d, J = 4.5Hz, 3H).

Example 4 (16): 4- (4-amino-2-chloro-5- (methylthio) phenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine Hydrochloride
LCMS retention time (minutes): 0.63;
MS (ESI, Pos.): 373 (M + H) ⁺ ;
¹ H-NMR (DMSO-d ₆ ): δ 9.08 (s, 1H), 8.43 (s, 2H), 7.40 (s, 1H), 6.93 (s, 1H), 2.37 (s, 3H).

Examples 4 (17) to 4 (24)
4- (4-Amino-2-fluoro-5- (methylthio) phenyl) -7- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole-4-yl) isoxazolo [4,5- c] A compound corresponding to the substitute for pyridine-3-amine was prepared by the same procedure as described in Example 4, and then reverse phase HPLC (column used: YMC Triart C18 (30 mm × 75 mm); mobile phase: 0). Purification with 1% TFA / water / acetonitrile = 95: 5-60: 40) gave the compound of the present invention having the following physical properties.

Example 4 (17): 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluoro-N- Methylbenzamide trifluoroacetate
LCMS retention time (minutes): 0.66;
MS (ESI, Pos.): 368 (M + H) ⁺ ;
^{1 1} H-NMR (DMSO-d ₆ ): δ (rotorer mixture) 8.98 (s, 1H), 8.35 (s, 2H), 8.27-8.21 (m, 1H), 7.76 (d, J = 8.5Hz, 1H) , 6.61 (d, J = 12.5Hz, 1H), 5.69 (br s, 2H), 2.71 (s, 1.5H), 2.69 (s, 1.5H).

Example 4 (18): 4- (4-amino-5- (ethylthio) -2-fluorophenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine Trifluoroacetate
LCMS retention time (minutes): 0.64;
MS (ESI, Pos.): 371 (M + H) ⁺ ;
^{1 1} H-NMR (CD ₃ OD): δ 8.97 (s, 1H), 8.43 (s, 2H), 7.69 (d, J = 8.0Hz, 1H), 6.73 (d, J = 12.5Hz, 1H), 2.81 (q, J = 7.0Hz, 2H), 1.25 (t, J = 7.0Hz, 3H).

Example 4 (19): 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluoro-N- Propylbenzamide trifluoroacetate
LCMS retention time (minutes): 0.84;
MS (ESI, Pos.): 396 (M + H) ⁺ ;
^{1 1} H-NMR (CD ₃ OD): δ 8.82 (s, 1H), 8.31 (s, 2H), 7.67 (d, J = 8.0 Hz, 1H), 7.56 (d, J = 12.5 Hz, 1H), 3.26 -3.13 (m, 2H), 1.53-1.48 (m, 2H), 0.86 (t, J = 7.0 Hz, 3H).

Example 4 (20): 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) benzamide trifluoroacetate
LCMS retention time (minutes): 0.67;
MS (ESI, Pos.): 336 (M + H) ⁺ ;
^{1 1} H-NMR (CD ₃ OD): δ 8.79 (s, 1H), 8.29 (s, 2H), 7.95 (d, J = 2.0Hz, 1H), 7.55 (dd, J = 8.5, 2.0Hz, 1H) , 6.88 (d, J = 8.5 Hz, 1H).

Example 4 (21): 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -N-ethylbenzamide trifluoro Acetate
LCMS retention time (minutes): 0.55;
MS (ESI, Pos.): 364 (M + H) ⁺ ;
¹ H-NMR (DMSO-d ₆ ): δ 8.96 (s, 1H), 8.37 (s, 2H), 8.30 (t, J = 6.0Hz, 1H), 7.96 (d, J = 2.5Hz, 1H), 7.57 (dd, J = 11.5, 2.5Hz, 1H), 6.88 (d, J = 11.5Hz, 1H), 5.84 (brs, 2H), 3.25 (qd, J = 9.0, 6.0Hz, 2H), 1.10 (t) , J = 9.0Hz, 3H).

Example 4 (22): 1- (2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) phenyl) propane- 1-one trifluoroacetate
HPLC retention time (minutes): 0.62;
MS (ESI, Pos.): 349 (M + H) ⁺ ;
¹ H-NMR (DMSO-d ₆ ): δ 8.97 (s, 1H), 8.37 (s, 2H), 8.33 (s, 1H), 8.25 (d, J = 2.0Hz, 1H), 7.76 (dd, J) = 9.0, 2.0Hz, 1H), 6.96 (d, J = 9.0Hz, 1H), 6.46 (br s, 2H), 5.94 (brs, 2H), 3.06 (q, J = 7.0Hz, 2H), 1.10 ( t, J = 7.0Hz, 3H).

Example 4 (23): 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-chloro-N- Ethylbenzamide trifluoroacetate
LCMS retention time (minutes): 0.59;
MS (ESI, Pos.): 398 (M + H) ⁺ ;
¹ H-NMR (DMSO-d ₆ ): δ 9.00 (s, 1H), 8.38 (s, 2H), 8.32 (t, J = 6.5Hz, 1H), 7.71 (s, 1H), 6.95 (s, 1H) ), 5.54 (brs, 2H), 3.23 (qd, J = 10.0, 6.5Hz, 2H), 1.08 (t, J = 10.0Hz, 3H).

Example 4 (24): 4- (2-fluoro-5-methoxy-4-nitrophenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine trifluoro Acetate
LCMS retention time (minutes): 0.92;
MS (ESI, Pos.): 371 (M + H) ⁺ .

Example 4 (25): 4- (4-Amino-2-fluoro-5- (trifluoromethyl) phenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] Pyridine-3 - amine 4- (4-amino-2-fluoro-5- (methylthio) phenyl) -7- (1- (tetrahydro -2H- pyran-2-yl)-1H-pyrazol-4-yl) isoxazolo [4, 5-c] After producing a compound corresponding to the substitute for pyridine-3-amine by the same procedure as described in Example 4, reverse phase HPLC (column used: Xtimate C18 (25 mm × 150 mm); mobile phase: Purification with 0.225% formic acid / water / acetonitrile = 75: 25-45: 55) gave the compound of the present invention having the following physical properties.
LCMS retention time (minutes): 0.90;
MS (ESI, Pos.): 379 (M + H) ⁺ ;
^{1 1} H-NMR (DMSO-d ₆ ): δ 8.93 (s, 1H), 8.39 (s, 2H), 7.69 (d, J = 7.5Hz, 1H), 6.78 (d, J = 12.5Hz, 1H).

Example 5: 4- (4-amino-2-fluoro-5- (methylsulfinyl) phenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine trifluoro Acetate The compound prepared in Example 4 (17.2 mg), sodium tetrahydrate tetrahydrate (6.16 mg), acetic acid (0.5 mL) and methanol (0.2 mL) are mixed and heated at 50 ° C. for 6 hours. Stirred. The reaction mixture was purified by reverse phase HPLC (column used: YMC Triart C18 (30 mm × 75 mm); mobile phase: 0.1% TFA / water / acetonitrile = 95: 5-60: 40) and had the following physical properties. The compound of the present invention (5.0 mg) was obtained.
LCMS retention time (minutes): 0.50;
MS (ESI, Pos.): 373 (M + H) ⁺ ;
^{1 1} H-NMR (DMSO-d ₆ ): δ 8.99 (s, 1H), 8.37 (s, 2H), 7.56 (d, J = 8.0Hz, 1H), 6.66 (d, J = 12.5Hz, 1H), 2.79 (s, 3H).

Example 6: 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorobenzoic acid In Example 1. THF (0.2 mL) and methanol (0.1 mL) were added to the produced compound (20 mg), a 2.0 mol / L sodium hydroxide aqueous solution (81 μL) was added dropwise at room temperature, and the mixture was stirred for 3 hours. The reaction mixture was neutralized and purified by reverse phase HPLC (column used: YMC Triart C18 (30 mm × 75 mm); mobile phase: 0.1% TFA / water / acetonitrile = 95: 5-60: 40). The compound of the present invention (12.1 mg) having a physical property value was obtained.
LCMS retention time (minutes): 0.53;
MS (ESI, Pos.): 355 (M + H) ⁺ ;
¹ H-NMR (DMSO-d ₆ ): δ 8.97 (s, 1H), 8.35 (s, 2H), 7.93 (d, J = 8.5Hz, 1H), 7.23 (br s, 1H), 6.67 (d, J = 12.5Hz, 1H), 5.72 (br s, 2H).

Example 7: 4- (4-Amino-2-fluoro-5-methoxyphenyl) -7- (3-methyl-1H-pyrazole-4-yl) isoxazolo [4,5-c] Pyridine-3-amine tri Fluoroacetate 1- (tetrahydro-2H-pyran-2-yl) -4- (4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole instead Using (1- (tert-butoxycarbonyl) -3-methyl-1H-pyrazole-4-yl) boronic acid, perform the same operation as in Reference Example 6 → Reference Example 13 → Example 2 to obtain the following physical property values. Obtained the compound of the present invention having.
LCMS retention time (minutes): 0.56;
MS (ESI, Pos.): 355 (M + H) ⁺ .

Example 8: 1- (2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-hydroxyphenyl) ethane -1-one trifluoroacetate Salt 1- (2-amino-5- (3-amino-7- (1- (tetrahydro-2H-pyran-2-yl) -1H-) produced in the step described in Example 3) Pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorophenyl) ethane-1-one (150 mg) in 1,3-dimethyl-2-imidazolidinone (3 mL) Acethydroxamic acid (258 mg) and potassium carbonate (618 mg) were added thereto, and the mixture was stirred at 80 ° C. for 5 hours. After cooling to room temperature, city water (15 mL) was added, and the mixture was extracted with ethyl acetate (20 mL). After washing with saturated brine, the mixture was concentrated. The residue was purified by silica gel column chromatography (Hi-flash NH) (ethyl acetate: methanol = 100: 0-50: 50) and 1- (2-amino-5- (3-amino-7- (1- (1). Tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-hydroxyphenyl) ethane-1-one (50 mg) was obtained. ..

Methanol (2.0 mL) and methanesulfonic acid (34 mg) were added to this compound (50 mg), and the mixture was stirred at room temperature for 64 hours. The precipitate formed after the reaction was collected by filtration and dissolved in dimethyl sulfoxide for reverse phase HPLC (column used: YMC Triart C18 (30 mm × 75 mm); mobile phase: 0.1% TFA / water / acetonitrile = 95: 5-60. : 40) was purified to obtain the compound of the present invention (23.1 mg) having the following physical property values.
LCMS retention time (minutes): 0.55;
MS (ESI, Pos.): 351 (M + H) ⁺ .

Reference Example 14: 5-Bromo-2-chloro-3-fluoroisonicotinonitrile

5-Bromo-2-chloro-3-fluoropyridine (CAS No. 831203-13-5) was used instead of 2-chloro-4-fluoro-5-iodopyridine, and the same as in Reference Example 1 → Reference Example 2. The title compound having the following physical property values was obtained.
^{1 1} H-NMR (DMSO-d ₆ ): δ 8.81 (s, 1 H).

Reference Example 15: 5- (4-Amino-2-fluoro-5-methoxyphenyl) -2-chloro-3-fluoroisonicotinonitrile

In an argon atmosphere, 5-fluoro-2-methoxy-4- (4,4,5,5-tetra) was added to a 1,4-dioxane solution (2.0 mL) of the compound (61.0 mg) prepared in Reference Example 14. Methyl-1,3,2-dioxaborolan-2-yl) aniline (CAS No.1326283-60-6) (70.0 mg), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (19.0 mg) and a 2 mol / L tripotassium phosphate aqueous solution (0.40 mL) were added, and the mixture was stirred at 90 ° C. for 3 hours. After allowing to cool, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Hi-flash SI) (hexane: ethyl acetate = 100: 0-30: 70) to give the title compound (45.0 mg) having the following physical characteristics.
MS (ESI, Pos.): 296 (M + H) ⁺ ;
^{1 1} H-NMR (CDCl ₃ ): δ8.41 (s, 1H), 6.76 (d, J = 6.5Hz, 1H), 6.55 (d, J = 11.5Hz, 1H), 4.25 (s, 2H), 3.88 (s, 3H).

Reference Example 16: 5- (4-amino-2-fluoro-5-methoxyphenyl) -3-fluoro-2- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole-4-yl) Isonicotinonitrile

Under an argon atmosphere, 4- (5,5-dimethyl-1,3,2-dioxaborinan-2-yl) was added to a 1,4-dioxane solution (2.0 mL) of the compound (45.0 mg) prepared in Reference Example 15. ) -1- (Tetrahydro-2H-pyran-2-yl) -1H-pyrazole (CAS No.1072944-26-3) (40.0 mg), [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) Dichloride (11.0 mg) and a 2 mol / L tripotassium phosphate aqueous solution (0.20 mL) were added, and the mixture was stirred at 110 ° C. for 6 hours. After allowing to cool, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Hi-flash SI) (hexane: ethyl acetate = 100: 0 to 15:85) to give the title compound (30.0 mg) having the following physical characteristics.
MS (ESI, Pos.): 412 (M + H) ⁺ ;
¹ H-NMR (CDCl ₃ ): δ 8.57 (dd, J = 1.5, 0.5Hz, 1H), 8.30 (d, J = 2.0Hz, 1H), 8.23 (d, J = 1.0 Hz, 1H), 6.81 ( d, J = 6.5Hz, 1H), 6.56 (d, J = 11.0Hz, 1H), 5.49-5.44 (m, 1H), 4.19 (s, 2H), 4.13-4.07 (m, 1H), 3.89 (s) , 3H), 3.79-3.71 (m, 1H), 2.17-2.05 (m, 3H), 1.80-1.62 (m, 3H).

Reference Example 17: 4- (4-Amino-2-fluoro-5-methoxyphenyl) -7- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole-4-yl) isoxazolo [5, 4-c] Pyridine-3-amine

Potassium tert-butoxide (89.0 mg) at room temperature was added to a solution of acetohydroxamic acid (59 mg) in DMF (1.0 mL) under a nitrogen atmosphere, and the mixture was stirred for 30 minutes. A solution of the compound (65 mg) prepared in Reference Example 16 in DMF (2.0 mL) was added dropwise to this mixed solution, and the mixture was stirred at room temperature for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Hi-flash SI) (hexane: ethyl acetate = 100: 0 to 15:85) to obtain the title compound (22.0 mg) having the following physical characteristics.
MS (ESI, Pos.): 425 (M + H) ⁺ ;
¹ H-NMR (CDCl ₃ ): δ 8.56 (s, 1H), 8.42 (s, 1H), 8.31 (d, J = 0.5Hz, 1H), 6.76 (d, J = 6.5Hz, 1H), 6.59 ( d, J = 10.5Hz, 1H), 5.52-5.47 (m, 1H), 4.14-4.08 (m, 1H), 4.33 (s, 2H), 4.15 (s, 2H), 3.87 (s, 3H), 3.79 -3.70 (m, 1H), 2.16-2.04 (m, 3H), 1.75-1.50 (m, 3H).

Example 9: 4- (4-amino-2-fluoro-5-methoxyphenyl) -7- (1H-pyrazole-4-yl) isoxazolo [5,4-c] pyridin-3-amine hydrochloride

Hydrochloric acid (1.25 mol / L methanol solution) (0.64 mL) was added to a THF solution (1.0 mL) of the compound (20.0 mg) prepared in Reference Example 17 at room temperature, and the mixture was stirred for 3 hours. The reaction solution was concentrated to obtain the compound of the present invention (5.8 mg) having the following physical characteristics.
LCMS retention time (minutes): 0.66;
MS (ESI, Pos.): 341 (M + H) ⁺ ;
^{1 1} H-NMR (CD ₃ OD): δ 8.45 (s, 2H), 8.24 (d, J = 1.0Hz, 1H), 6.92 (d, J = 7.0 Hz, 1H), 6.70 (d, J = 11.5Hz) , 1H), 3.89 (s, 3H).

Reference Example 18: Methyl 2-amino-5-(3-amino-7- (1-(((di-tert-butoxyphosphoryl) oxy) methyl) -1H-pyrazole-4-yl) isoxazolo [4,5- c] Pyridine-4-yl) -4-fluorobenzoate

Cesium carbonate (6.61 g) and di-tert-butyl-chloromethyl phosphate (1.41 mL) were added to a DMF solution (41 mL) of the compound (1.49 g) prepared in Example 1 at 50 ° C. for 5 hours. Stirred. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Hi-flash SI) (hexane: ethyl acetate = 90: 10-0: 100) to give the title compound (1.14 g) having the following physical characteristics.
LCMS retention time (minutes): 0.84;
MS (ESI, Pos.): 591 (M + H) ⁺ .

Example 10: Methyl 2-amino-5- (3-amino-7- (1-((phosphonooxy) methyl) -1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-Fluorobenzoate

Purified water (6.8 mL) and acetic acid (13.5 mL) were added to the compound (1.09 g) prepared in Reference Example 18, and the mixture was stirred at 50 ° C. overnight. The precipitate precipitated after the reaction was collected by filtration. The filter is purified by reverse phase HPLC (column used: YMC Triart C18 (50 mm × 100 mm); mobile phase: 0.1% TFA / water / acetonitrile = 95: 5 to 50:50), and concentrated to obtain the following physical properties. The compound of the present invention (536 mg) having a value was obtained.
LCMS retention time (minutes): 0.51;
MS (ESI, Pos.): 479 (M + H) ⁺ ;
¹ H-NMR (DMSO-d ₆ ): δ 8.99 (s, 1H), 8.63 (s, 1H), 8.35 (s, 1H), 7.94 (d, J = 8.5Hz, 1H), 7.21 (brs, 2H) ), 6.71 (d, J = 12.5Hz, 1H), 5.91 (d, J = 10.0Hz, 2H), 5.75 (brs, 2H), 3.82 (s, 3H).

Examples 10 (1) to 10 (12)
Substitute for methyl 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorobenzoate prepared in Example 1. The compound of the present invention having the following physical property values was obtained by performing the same operation as in Reference Example 18 → Example 10 using the compound corresponding to.

Example 10 (1): (4- (4- (5-Acetyl-4-amino-2-fluorophenyl) -3-aminoisoxazolo [4,5-c] Pyridine-7-yl) -1H- Pyrazole-1-yl) methyl dihydrogen phosphate

Cesium carbonate (91.9 mg) and di-tert-butyl-chloromethyl phosphate (20 μL) were added to a solution of the compound (24 mg) prepared in Example 3 in DMF (0.5 mL), and the mixture was stirred at room temperature for 8 hours. City water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. Dichloromethane (0.30 mL) and trifluoroacetic acid (0.12 mL) were added to the residue, and the mixture was stirred at 40 ° C. overnight. The reaction mixture is diluted with DMSO and purified by reverse phase HPLC (column used: YMC Triart C18 (30 mm × 75 mm); mobile phase: 0.1% TFA / water / acetonitrile = 95: 5-60: 40). A compound of the present invention (3.9 mg) having the following physical properties was obtained.
LCMS retention time (minutes): 0.50;
MS (ESI, Pos.): 463 (M + H) ⁺ ;
¹ H-NMR (DMSO-d ₆ ): δ8.98 (s, 1H), 8.61 (s, 1H), 8.33 (s, 1H), 7.97 (d, J = 8.5Hz, 1H), 7.70 (brs, brs, 2H), 6.65 (d, J = 13.0Hz, 1H), 5.89 (d, J = 10.0Hz, 2H), 5.76 (brs, 2H), 2.51 (s, 3H).

Example 10 (2): Ethyl 2-amino-5- (3-amino-7- (1-((phosphonooxy) methyl) -1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridine-4 -Il) -4-fluorobenzoate

Cesium carbonate (128 mg) and di-tert-butyl-chloromethyl phosphate (27 μL) were added to a solution of compound (36 mg) prepared in Example 4 (6) in DMF (0.5 mL), and the mixture was stirred overnight at room temperature. City water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. Dichloromethane (0.30 mL) and trifluoroacetic acid (0.18 mL) were added to the residue, and the mixture was stirred at 40 ° C. for 3.5 hours. The reaction mixture is diluted with DMSO and purified by reverse phase HPLC (column used: YMC Triart C18 (30 mm × 75 mm); mobile phase: 0.1% TFA / water / acetonitrile = 95: 5-60: 40). A compound of the present invention (15.0 mg) having the following physical properties was obtained.
LCMS retention time (minutes): 0.55;
MS (ESI, Pos.): 493 (M + H) ⁺ ;
¹ H-NMR (DMSO-d ₆ ): δ 8.97 (s, 1H), 8.60 (s, 1H), 8.31 (s, 1H), 7.93 (d, J = 8.5Hz, 1H), 7.19 (br s, 2H), 6.67 (d, J = 12.5Hz, 1H), 5.87 (d, J = 10.0Hz, 2H), 5.73 (brs, 2H), 4.26 (q, J = 7.0Hz, 2H), 1.27 (t, J = 7.0Hz, 3H).

Example 10 (3): (4- (3-Amino-4- (4-amino-5- (ethylcarbamoyl) -2-fluorophenyl) isoxazolo [4,5-c] pyridin-7-yl) -1H -Pyrazole-1-yl) Methyl dihydrogen phosphate

LCMS retention time (minutes): 0.50;
MS (ESI, Pos.): 492 (M + H) ⁺ .
¹ H-NMR (DMSO-d ₆ ): δ 8.99 (s, 1H), 8.61 (s, 1H), 8.33 (s, 1H), 8.27 (t, J = 5.5Hz, 1H), 7.78 (d, J) = 8.5Hz, 1H), 7.13 (brs, 2H), 6.60 (d, J = 12.5Hz, 1H), 5.88 (d, J = 10.0Hz, 2H), 5.65 (brs, 2H), 3.26-3.18 (m) , 2H), 1.07 (t, J = 7.0Hz, 3H).

Example 10 (4): (4- (3-Amino-4- (4-amino-2-fluoro-5- (methylthio) phenyl) isoxazolo [4,5-c] pyridin-7-yl) -1H- Pyrazole-1-yl) methyl dihydrogen phosphate

LCMS retention time (minutes): 0.52;
MS (ESI, Pos.): 467 (M + H) ⁺ ;
¹ H-NMR (DMSO-d ₆ ): δ8.96 (s, 1H), 8.60 (s, 1H), 8.32 (s, 1H), 7.40 (d, J = 8.5Hz, 1H), 6.62 (d, J = 12.5Hz, 1H), 5.95 (brs, 2H), 5.88 (d, J = 10.0Hz, 2H), 5.64 (s, 2H), 2.32 (s, 3H).

Example 10 (5): (4- (3-Amino-4- (4-amino-2-fluoro-5-propionylphenyl) isoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazole- 1-yl) methyl dihydrogen phosphate

LCMS retention time (minutes): 0.53;
MS (ESI, Pos.): 477 (M + H) ⁺ ;
¹ H-NMR (DMSO-d ₆ ): δ8.98 (s, 1H), 8.61 (s, 1H), 8.33 (s, 1H), 7.99 (d, J = 8.5Hz, 1H), 7.70 (brs, 2H), 6.66 (d, J = 12.0Hz, 1H), 5.88 (d, J = 10.0Hz, 2H), 5.75 (brs, 2H), 2.96 (q, J = 7.5Hz, 2H), 1.05 (t, J = 7.5Hz, 3H).

Example 10 (6): (4- (4- (3-Acetyl-4-aminophenyl) -3-aminoisoxazolo [4,5-c] Pyridine-7-yl) -1H-pyrazole-1- Il) Methyl dihydrogen phosphate

LCMS retention time (minutes): 0.48;
MS (ESI, Pos.): 445 (M + H) ⁺ ;
¹ H-NMR (DMSO-d ₆ ): δ8.95 (s, 1H), 8.58 (s, 1H), 8.31 (s, 1H), 8.19 (d, J = 2.0Hz, 1H), 7.77 (dd, dd, J = 8.5, 2.0Hz, 1H), 7.58 (brs, 2H), 6.92 (d, J = 8.5Hz, 1H), 5.92-5.85 (m, 4H), 2.54 (s, 3H).

Example 10 (7): (4- (3-Amino-4- (4-amino-2-fluoro-5- (methylsulfonyl) phenyl) isoxazolo [4,5-c] pyridin-7-yl) -1H -Pyrazole-1-yl) Methyl dihydrogen phosphate

LCMS retention time (minutes): 0.668;
MS (ESI, Pos.): 499 (M + H) ⁺ ;
¹ H-NMR (DMSO-d ₆ ): δ9.00 (s, 1H), 8.63 (s, 1H), 8.35 (s, 1H), 7.74 (d, J = 8.0Hz, 1H), 6.79 (d, J = 12.0Hz, 1H), 6.64 (brs, 2H), 5.91 (d, J = 12.0Hz, 2H), 5.83 (brs, 2H), 3.18 (s, 3H).

Example 10 (8): (4- (3-Amino-4- (4-amino-5- (ethylcarbamoyl) -2-chlorophenyl) isoxazolo [4,5-c] pyridin-7-yl) -1H- Pyrazole-1-yl) methyl dihydrogen phosphate acetate or acetic acid sum

By subjecting the compound (421 mg) prepared in Example 4 (23) to the same operation as in Reference Example 18, (4- (3-amino-4- (4-amino-2-chloro-5-) (ethylcarbamoyl)) ) Phenyl) isoxazolo [4,5-c] pyridine-7-yl) -1H-pyrazole-1-yl) methyldi-tert-butyl phosphate (430 mg) was obtained. Acetic acid (19.3 mL) and purified water (3.4 mL) were added to this compound (379 mg), and the mixture was stirred at 60 ° C. for 5 hours. The obtained precipitate was collected by filtration and dried to obtain the compound of the present invention (304 mg) having the following physical properties and in the form of an acetate or acetic acid sum.
LCMS retention time (minutes): 0.706;
MS (ESI, Pos.): 508 (M + H) ⁺ ;
¹ H-NMR (DMSO-d ₆ ): δ9.01 (s, 1H), 8.64 (s, 1H), 8.36 (s, 1H), 8.33-8.29 (m, 1H), 7.70 (s, 1H), 7.01 (brs, 2H), 6.94 (s, 1H), 5.90 (d, J = 10.0Hz, 2H), 5.53 (brs, 2H), 3.24-3.18 (m, 2H), 1.91 (s, 3H), 1.07 (t, J = 7.0Hz, 3H).

Example 10 (9): (4- (4- (5-Acetyl-4-amino-2-fluorophenyl) -3-aminoisoxazolo [4,5-c] Pyridine-7-yl) -1H- Hydrate of pyrazole-1-yl) methyl dihydrogen phosphate By subjecting the compound (100 mg) prepared in Example 3 to the same procedure as in Reference Example 18, (4- (4- (5-acetyl-4-) Amino-2-fluorophenyl) -3-aminoisoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazole-1-yl) methyldi-tert-butyl phosphate (112 mg) was obtained. Acetic acid (0.20 mL) and purified water (0.05 mL) were added to this compound (25 mg), and the mixture was stirred at 60 ° C. overnight. The obtained precipitate was collected by filtration and dried to obtain the compound of the present invention (18.0 mg) of Example 10 (1) having the following physical property values and in the form of a hydrate. From the DSC and TG analysis of the compound of the present invention, it was confirmed that it was a hydrate.
LCMS retention time (minutes): 0.50;
MS (ESI, Pos.): 463 (M + H) ⁺ ;
¹ H-NMR (DMSO-d ₆ ): δ8.98 (s, 1H), 8.61 (s, 1H), 8.33 (s, 1H), 7.97 (d, J = 8.5Hz, 1H), 7.70 (brs, brs, 2H), 6.65 (d, J = 13.0Hz, 1H), 5.89 (d, J = 10.0Hz, 2H), 5.76 (brs, 2H), 2.51 (s, 3H).

Example 10 (10): (4- (4- (5-Acetyl-4-amino-2-fluorophenyl) -3-aminoisoxazolo [4,5-c] Pyridine-7-yl) -1H- Pyrazole-1-yl) methyl monohydrogen phosphate monopotassium salt A 0.25M potassium acetate aqueous solution (0.43 mL, 1 equivalent) in an acetic acid (1.25 mL) solution of the compound (50 mg) prepared in Example 10 (1). Was added, and the mixture was stirred at room temperature for 8 hours. The obtained suspension was collected by filtration and dried under reduced pressure to obtain a compound of the present invention (43.5 mg) having the following physical characteristics.
LCMS retention time (minutes): 0.49;
MS (ESI, Pos.): 463 (M + H) ⁺ ;
^{1 1} H-NMR (DMSO-d ₆ + CD ₃ OD): δ8.94 (s, 1H), 8.60 (s, 1H), 8.21 (s, 1H), 7.99 (d, J = 8.5Hz, 1H), 7.70 (brs, 2H), 6.66 (d, J = 13.0Hz, 1H), 5.69 (d, J = 9.5Hz, 2H), 2.52 (s, 3H).

Example 10 (11): Ethyl 2-amino-5- (3-amino-7- (1-((phosphonooxy) methyl) -1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridine-4 -Il) -4-fluorobenzoate trifluoroacetic acid salt or trifluoroacetic acid sum product In a DMF (0.5 mL) solution of the compound (2.00 g) prepared in Example 4 (6), cesium carbonate (128 mg) and Di-tert-butyl-chloromethyl phosphate (27 μL) was added and stirred overnight at room temperature. City water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (Hi-flash SI) (hexane: ethyl acetate = 90: 10-0: 100) and ethyl 2-amino-5- (3-amino-7- (1-((((((). Di-tert-butoxyphosphoryl) oxy) methyl) -1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorobenzoate (2.12 g) was obtained. Purified water (10 mL), ethanol (10 mL) and trifluoroacetic acid (5.3 mL) were sequentially added thereto, and the mixture was stirred at 40 ° C. After 2 hours, ethanol (5 mL) was added and the mixture was cooled to room temperature. The obtained precipitate was collected by filtration while washing with ethanol and dried under reduced pressure to obtain the compound of the present invention (1.81 g) having the following physical characteristics.
LCMS retention time (minutes): 0.55;
MS (ESI, Pos.): 493 (M + H) ⁺ ;
¹ H-NMR (DMSO-d ₆ ): δ 9.02 (s, 1H), 8.65 (s, 1H), 8.36 (s, 1H), 7.98 (d, J = 8.5Hz, 1H), 7.32 (brs, 2H) ), 6.70 (d, J = 12.5Hz, 1H), 5.91 (d, J = 10.0Hz, 2H), 5.79 (brs, 2H), 4.28 (q, J = 7.0Hz, 2H), 1.29 (t, J) = 7.0Hz, 3H).

Example 10 (12): Ethyl 2-amino-5- (3-amino-7- (1-((phosphonooxy) methyl) -1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridine-4 -Il) -4-fluorobenzoate acetate or acetic acid sum product Purified water (30 mL) and acetic acid (20 mL) were added to the compound (2.13 g) prepared in Example 10 (2), and the temperature was 60 ° C. for 4 hours. Stirred. The solvent was evaporated under reduced pressure and diluted with ethanol (30 mL). The reaction mixture was stirred overnight and collected by filtration to obtain the compound of the present invention (1.50 g) having the following physical characteristics.
LCMS retention time (minutes): 0.55;
MS (ESI, Pos.): 493 (M + H) ⁺ ;
¹ H-NMR (DMSO-d ₆ ): δ8.99 (s, 1H), 8.62 (s, 1H), 8.34 (s, 1H), 7.96 (d, J = 8.5Hz, 1H), 7.21 (brs, brs, 2H), 6.69 (d, J = 13.0Hz, 1H), 5.91 (d, J = 10.0Hz, 2H), 5.74 (brs, 2H), 4.27 (q, J = 7.0Hz, 2H), 1.92 (s, 3H), 1.29 (t, J = 7.0Hz, 3H).

Reference Example 19: 4-Chloro-7-iodoisothiazolo [4,5-c] Pyridine-3-amine

Under a nitrogen atmosphere, dimethyl sulfoxide was added to sodium sulfide (138 mg) and stirred for 10 minutes, then the compound (500 mg) prepared in Reference Example 2 was added and stirred at room temperature for 30 minutes. After cooling to 10 ° C., aqueous ammonia was added and the mixture was stirred for 30 minutes. N-Chlorosuccinimide (248 mg) was added and stirred for 30 minutes, and then N-chlorosuccinimide (472 mg) was further added and stirred for 30 minutes. Saturated aqueous sodium thiosulfate solution (5 mL) and city water (15 mL) were added, and the precipitate was collected by filtration. The precipitate was dried at 50 ° C. for 1.5 hours, dissolved in ethyl acetate, and washed with city water. After drying over sodium sulfate, the mixture was concentrated to give the title compound (286 mg) having the following physical characteristics.
LCMS retention time (minutes): 0.88;
MS (ESI, Pos.): 312 (M + H) ⁺ ;

Reference Example 20: 4-Bromo-7-iodoisothiazolo [4,5-c] Pyridine-3-amine

Propionitrile (2.4 mL) and bromotrimethylsilane (0.61 mL) were added to the compound (240 mg) prepared in Reference Example 19 under a nitrogen atmosphere, and the mixture was stirred at 100 ° C. for 20 hours. After cooling to 0 ° C., methyl tert-butyl ether (7.2 mL) was added and the mixture was stirred for 1.5 hours. The precipitate was collected by filtration to obtain the title compound (317 mg) having the following physical characteristics.
LCMS retention time (minutes): 0.91;
MS (ESI, Pos.): 356 (M + H) ⁺ ;

Reference Example 21: 4-Bromo-7- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole-4-yl) isothiazolo [4,5-c] pyridin-3-amine

Compound (384 mg), 1- (tetrahydro-2H-pyran-2-yl) -4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane) prepared in Reference Example 20 under a nitrogen atmosphere. -2-yl) -1H-pyrazole (315 mg) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex (66 mg) in a mixture of 1,4-dioxane (4.6 mL) and 2 mol. / L A tripotassium phosphate aqueous solution (1.6 mL) was added, and the mixture was stirred at 105 ° C. for 29 hours. After cooling to room temperature, ethyl acetate and city water were added, and the mixed solution was filtered through Celite (trade name). After extraction with ethyl acetate, it was concentrated. The residue was purified by silica gel column chromatography (Hi-flash DIOL) (ethyl acetate: hexane = 75: 25-50: 50) to obtain the title compound (75.7 mg) having the following physical characteristics.
LCMS retention time (minutes): 0.86;
MS (ESI, Pos.): 380 (M + H) ⁺ ;

Example 11: 1- (2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isothiazolo [4,5-c] pyridin-4-yl) -4-fluorophenyl) ethane -1-one trifluoroacetate

Boronic acid ester (69 mg) and butyldi-1-adamantylphosphine (8.9 mg) prepared in Reference Example 12 (3) were added to an NMP (1.25 mL) solution of the compound (75 mg) prepared in Reference Example 21 under a nitrogen atmosphere. ), Palladium acetate (2.8 mg), potassium iodide (2.7 mg) and a 2 mol / L tripotassium phosphate aqueous solution (0.17 mL) were added, and the mixture was stirred at 80 ° C. for 18 hours. After allowing the reaction solution to cool, it is directly purified by silica gel column chromatography (Hi-flash DIOL) (ethyl acetate: hexane = 80: 20-50: 50) and 1- (2-amino-5- (3-amino-). 7- (1- (Tetrahydro-2H-pyran-2-yl) -1H-pyrazole-4-yl) isothiazolo [4,5-c] pyridin-4-yl) -4-fluorophenyl) ethane-1-one (13 mg) was obtained.

Methanol (0.65 mL) and methanesulfonic acid (8.3 mg) were added to this compound (13 mg), and the mixture was stirred at room temperature for 3 hours. After allowing the reaction mixture to cool to room temperature, triethylamine (8.8 mg) was added and concentrated, and the residue was subjected to reverse phase HPLC (column used: YMC Triart C18 (30 mm × 75 mm); mobile phase: 0.1% TFA / water / Purification with acetonitrile = 95: 5-60: 40) gave the compound of the present invention (3.0 mg) having the following physical properties.
LCMS retention time (minutes): 0.60;
MS (ESI, Pos.): 369 (M + H) ⁺ ;
¹ H-NMR (DMSO-d ₆ ): δ8.83 (s, 1H), 8.32 (brs, 1H), 8.10 (brs, 1H), 7.94 (d, J = 8.5Hz, 1H), 7.69 (brs, 2H), 6.67 (d, J = 13.0Hz, 1H), 5.87 (s, 2H), 2.49 (s, 3H).

[Pharmacology Examples]
Example 12: Action on THP1-Dual cells THP1-Dual cells (Invivogen) were suspended in RPMI medium to prepare a 2 × 10 ⁶ cell / mL cell suspension. 50 μL of the cell suspension was dispensed into a 96-well plate, and 50 μL of a compound solution of 6 to 20,000 nmol / L was further added. After adding the compound, the mixture was incubated at 37 ° C. for about 24 hours. After incubation, 10 μL of cell suspension was collected from each well and mixed with 50 μL of Quanti-luc (Invivogen). Then, activation of the IRF (Interferon regulatory factor) pathway was measured by detecting luminescence using a microplate reader (Molcular Devices).

The EC50 values of the compounds of the present invention shown in each example are shown below.

Example 13: Action on THP1-Dual-STING KO cells THP1-Dual cells homozygous for the STING gene (THP1-Dual-STING KO cells (Invivogen)) were suspended in RPMI medium and 2 × 10 ⁶ cells / mL. The cell suspension was prepared. 50 μL of the cell suspension was dispensed into a 96-well plate, and 50 μL of a compound solution of 6 to 20,000 nM was further added. After the compound was added, the temperature was 37 ° C. for about 24 hours. Incubated. After incubation, 10 μL of cell suspension was collected from each well and mixed with 50 μL of Quanti-luc (Invivogen). Then, the activity of the IRF pathway was detected by detecting luminescence using a microplate reader. The conversion was measured.

The compound of the present invention shown in Example 1 did not show an IRF activating effect. Therefore, it was shown that the IRF activating action of the compound of the present invention exemplified in Example 1 is based on the working activity of the compound of the present invention on STING.

Example 14: Evaluation of IDO1 inhibitory activity The evaluation of IDO1 inhibitory activity was carried out using the IDO1 Fluorogenic Inhibitor Screening Assay Kit (BPS Bioscience). Specifically, IDO1 Fluorogenic Reaction Solution was dissolved and 180 μL was added to each well. Next, 10 μL of compounds having concentrations of 0.6, 2, 6, 20, 60 and 200 μmol / L was added. Further, 10 μL of IDO1 His-Tag solution was added, and then the mixture was incubated at room temperature for 1 hour. Next, 20 μL of Fluorescence Solutioon was added and incubated at 37 ° C. for 4 hours. After allowing to stand at room temperature for 10 minutes, fluorescence was measured using a microplate reader (excitation: 400 nm, emission: 510 nm).

The compound of the present invention shown in Example 1 did not show IDO1 inhibitory activity.

Example 15: Evaluation of inhibitory activity against various kinases A 4 μmol / L test substance (compound of the present invention shown in Example 1) solution (concentration 4 times the final concentration) was used in an assay buffer (20 mmol / L HEPES, 0.01% Triton X). It was prepared at -100, 1 mmol / L DTT, pH 7.5). A 4 μmol / L substrate / ATP / metal solution (4 times the final concentration) was prepared in kit buffer (20 mmol / L HEPES, 0.01% Triton X-100, 5 mmol / L DTT, pH 7.5). Various kinase solutions at twice the final concentration were prepared in assay buffer. 5 μL of the test substance solution, 5 μL of the substrate / ATP / metal solution and 10 μL of the kinase solution were mixed in wells of a polypropylene 384-well plate and reacted at room temperature for 1-5 hours. 70 μL of termination buffer (QuickScout Screening Assist MSA; Carna Biosciences) was added to terminate the reaction. The substrate peptide and phosphorylated peptide in the reaction solution were separated and quantified by the LabChip system (Perkin Elmer). The kinase reaction was evaluated by the product ratio (P / (P + S)) calculated from the substrate peptide peak height (S) and the phosphorylated peptide peak height (P). The various kinases used for the evaluation are as follows.
BTK, KDR, PKCα-ι subtypes, CDK2-9 CDK, FAK, TIE2, RAF1 and BRAF
The compound of the present invention shown in Example 1 did not show significant inhibitory activity against any of the evaluated kinases.

Example 16: Evaluation of antitumor effect in mouse colon cancer cell line MC38 subcutaneous cancer model C57 / BL6 mouse-derived colon cancer cell line MC38 was used in allogeneic mice (C57 / BL6, female, 6 weeks old (Charles River, Japan)) ) Was subcutaneously transplanted to the right abdomen (here, the transplantation date was set to Day 0) to prepare MC38 subcutaneous cancer-bearing mice. Seven days after transplantation, grouping was performed based on the tumor volume, and the MC38 subcutaneous cancer-bearing mice were subjected to the Vehicle group (n = 8) and the compound administration group shown in Example 1 (3 mg / kg, n = 6). It was set. Changes in tumor volume were measured over time until 26 days after transplantation (Day 26). The tumor volume was calculated from the following formula.
[Tumor volume (mm ³ )] = [major axis (mm)] x [minor axis (mm)] ² x 0.5
The result is shown in FIG.

The compound shown in Example 1 almost completely suppressed tumor growth at a dose of 3 mg / kg.

Example 17: Evaluation of antitumor effect in mouse colon cancer cell line MC38 subcutaneous cancer model C57 / BL6 mouse-derived colon cancer cell line MC38 was used in allogeneic mice (C57 / BL6, female, 6 weeks old (Charles River, Japan)) ) Was subcutaneously transplanted to the right abdomen (here, the transplantation date was set to Day 0) to prepare MC38 subcutaneous cancer-bearing mice. Seven or eight days after transplantation, grouping was performed based on tumor volume, and for MC38 subcutaneous cancer-bearing mice, shown in Vehicle (n = 8 or 6) and Examples 10 and 10 (1) to 10 (6). Each compound (1, 1, 1, 10, 3, 1 and 1 mg / kg, n = 8 or 6 respectively) was administered. Changes in tumor volume were measured over time until 28 or 30 days after transplantation (Day 28 or 30). The tumor volume was calculated from the formula shown in Example 16.

The results are shown in FIGS. 2 and 3.

All the compounds shown in Examples 10 and 10 (1) -10 (6) suppressed tumor growth at each of the above doses. That is, in each of the compound administration groups shown in Examples 10 and 10 (1) to 10 (6), the median tumor volume was less than 500 mm ³ even 30 days after transplantation.

[Formulation Example]
Formulation Example 1
Each of the following components is mixed by a conventional method and then tableted to obtain 10,000 tablets containing 5 mg of the active ingredient in one tablet.
Methyl 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorobenzoate 50 g
・ Carboxymethyl cellulose calcium 20g
・ Magnesium stearate 10g
・ Microcrystalline cellulose 920g
Preparation example 2
After mixing each of the following components by a conventional method, the solution is sterilized by a conventional method, 5 mL each is filled in an ampoule, and freeze-dried by a conventional method to obtain 10,000 ampoules containing 20 mg of the active ingredient in one ampoule. be able to.
-Methyl 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorobenzoate 200 g
・ Mannitol 20g
・ Distilled water 50L

Since the compound of the present invention has operative activity against STING, a drug containing it as an active ingredient is useful as an agent for suppressing the progression of cancer or an infectious disease, suppressing recurrence, and / or treating it.

[8-1] The other anticancer agent according to any one of the above items [2-3], [3-8] to [3-10] and [3-23] is an alkylating agent or a platinum preparation. , Antimetabolites (eg, antimetabolites, pyridine metabolism inhibitors and purine metabolism inhibitors), ribonucleotide reductase inhibitors, nucleotide analogs, topoisomerase inhibitors, microtubule polymerization inhibitors, microtubule depolymerization inhibitors, anti The pharmaceutical composition according to the preceding paragraph [2-3] or one or more agents selected from neoplastic antibiotics, cytokine preparations and antihormonal agents or the preceding paragraphs [3-8] to [3-10] and [3- 23] The agent according to any one of the above;
[8-2] The other anticancer agent according to any one of the preceding paragraphs [2-3], [3-8] to [3-10] and [3-23] is a molecular target drug. The pharmaceutical composition according to the preceding item [2-3] or the agent according to any one of the preceding items [3-8] to [3-10] and [3-23];
[8-3] Molecular-targeted agents include ALK inhibitors, BCR-ABL inhibitors, EGFR inhibitors, B-Raf inhibitors, VEGFR inhibitors, FGFR inhibitors, c-Met inhibitors, Axl inhibitors, and Mek inhibitors. Agent, CDK inhibitor, Btk inhibitor, PI3K-δ / γ inhibitor, JAK-1 / 2 inhibitor, TGFbR1 inhibitor, Cancer cell stemness kinase inhibitor, Syk / FLT3 dual inhibitor, ATR inhibitor, Wee1 kinase Inhibitor, multityrosine kinase inhibitor, mTOR inhibitor, HDAC inhibitor, PARP inhibitor, aromatase inhibitor, EZH2 inhibitor, galectin-3 inhibitor, STAT3 inhibitor, DNMT inhibitor, SMO inhibitor, Hsp90 inhibitor , Γ-Tubulin-specific inhibitor, HIF2α inhibitor, glutaminase inhibitor, E3 ligase inhibitor, Nrf2 activator, arginase inhibitor, cell cycle inhibitor, IAP antagonist, anti-Her2 antibody, anti-EGFR antibody, anti- VEGF antibody, anti-VEGFR2 antibody, anti-CD20 antibody, anti-CD30 antibody, anti-CD38 antibody, anti-DR5 antibody, anti-CA125 antibody, anti-DLL4 antibody, anti-fucosyl GM1 antibody, anti-gpNMB antibody, anti-Mesothelin antibody, anti-MMP9 antibody, anti-GD2 Antibodies, anti-c-Met antibody, anti-FOLR1 antibody, anti-Ang2-VEGF bispecific antibody, anti-CD30-CD16A bispecific antibody, anti-CD79b antibody, anti-FAP antibody / IL-2 fusion protein, anti-CEA antibody / One or more agents selected from IL-2 fusion protein, anti-CEA-CD3 bispecific antibody, anti-DLL3 antibody, anti-CD3-CD19 bispecific antibody and anti-CD20-CD3 bispecific antibody. The pharmaceutical composition according to the preceding item [8-2] or the agent according to the preceding item [8-2];
[8-4] The other anticancer agent according to any one of the above items [2-3], [3-8] to [3-10] and [3-23] is a cancer immunotherapeutic agent. A pharmaceutical composition according to the preceding paragraph [2-3] or an agent according to any one of the preceding paragraphs [3-8] to [3-10] and [3-23];
[8-5] Cancer immunotherapeutic agents include anti-PD-1 antibody, anti-PD-L1 antibody, PD-1 antagonist, PD-L1 / VISTA antagonist, PD-L1 / TIM3 antagonist, anti-PD-L2. Antibody, PD-L1 fusion protein, PD-L2 fusion protein, anti-CTLA-4 antibody, anti-LAG-3 antibody, LAG-3 fusion protein, anti-Tim3 antibody, anti-KIR antibody, anti-BTLA antibody, anti-TIGIT antibody, anti-VISTA Antibodies, anti-CD137 antibodies, anti-CSF-1R antibodies / CSF-1R inhibitors, anti-OX40 antibodies, anti-HVEM antibodies, anti-CD27 antibodies, anti-GITR antibodies, anti-CD28 antibodies, anti-CCR4 antibodies, anti-B7-H3 antibodies, anti-ICOS Amplifier antibody, anti-CD4 antibody, anti-DEC-205 antibody / NY-ESO-1 fusion protein, anti-SLAMF7 antibody, anti-CD73 antibody, anti-CD122 antibody, anti-CD40 agonist antibody, IDO inhibitor, TLR agonist, adenosine A2A receptor antagonism One or more agents selected from agents, anti-NKG2A antibodies, anti-CSF-1 antibodies, immunopotentiators, IL-15 super agonists, soluble LAG3, CD47 antagonists and IL-12 antagonists, the preceding paragraph [8-4]. ] The pharmaceutical composition or the agent according to the preceding paragraph [8-4];
[8-6] Anti-PD-1 antibodies include Nivolumab, Cemiplimab, Pembrolizumab, Spartanizumab, Tislelizumab, AMP-514, Dostarlimab, Tripalimab, Camrelizumab, Genolimzumab, Sintilimab, STI-A1110, ENUM 388D4, ENUM 244C8 AGEN2034, CS1003, HLX10, BAT-1306, AK105, AK103, BI 754091, LZM009, CMAB819, Sym021, GB226, SSI-361, JY034, HX008, ABBV181, BCD-100, ISU106, PF-06801591, CX-188, JNJ -The pharmaceutical composition according to the preceding paragraph [8-5] or the agent according to the preceding paragraph [8-5], which is an antibody selected from 63723283 and AB122;
[8-7] Anti-PD-L1 antibodies are Atezolizumab, Avelumab, Durvalumab, BMS-936559, STI-1014, KN035, LY3300054, HLX20, SHR-1316, CS1001, MSB2311, BGB-A333, KL-A167, CK- The pharmaceutical composition according to the preceding paragraph [8-5] or the agent according to the preceding paragraph [8-5], which is an antibody selected from 301, AK106, AK104, ZKAB001, FAZ053, CBT-502, JS003 and CX-072;

Here, the alkylation reaction is known, for example, in an organic solvent (for example, dichloromethane, chloroform, dioxane, ethyl acetate, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, etc.). , Inorganic bases (potassium carbonate, sodium carbonate, cesium carbonate, sodium hydroxide or potassium hydroxide, etc.) or organic bases (eg, triethylamine, N, N-diisopropylamine , lithium diisopropylamide, lithium bis (trimethylsilyl) amide, sodium bis Presence of (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, tert-butylimino-tris (dimethylamino) phosphorane, tert-butylimino-tri (pyrrolidino) phosphorane or 1,4-diazabicyclo [2.2.2] octane, etc.) Below, it is carried out by reacting X ¹ (CR ^Fb ₂ ) _q OP (= O) (OR ^Fa ') ₂ with a compound represented by the general formula (IV). Further, the deprotection reaction of ^'the R ^Fa when is a protecting ^group' R ^Fa also known, for example, a known deprotection reaction or palladium in acidic conditions - even in a hydrogenation reaction in the presence of such carbon catalyst Can be carried out. When R ^{Fa'represents} a protecting group, it corresponds to a protecting group of a hydroxyl group, for example, a methyl group, a trityl group, a methoxymethyl group, a 1-ethoxyethyl group, a methoxyethoxymethyl group, a 2-tetrahydropyranyl group, and the like. Trimethylsilyl group, triethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, acetyl group, pivaloyl group, benzoyl group, benzyl group, p-methoxybenzyl group, allyloxycarbonyl group or 2,2,2- Examples thereof include a trichloroethoxycarbonyl group. Further, the hydrogenation reaction in the presence of a palladium-carbon catalyst or the like is carried out in an organic solvent (for example, methanol, ethanol, tetrahydrofuran, dioxane, ethyl acetate, isopropyl alcohol, etc.) in a hydrogen gas atmosphere of 1 to 20 atm. It is carried out at room temperature to 120 ° C. in the presence of 0.01 to 100 mol% of catalyst (eg, palladium-carbon, platinum-carbon, palladium-carbon hydroxide or rhodium-carbon, etc.).

Claims (36)

General formula (I-1)

[In the equation, X and Y each represent -CH = or a nitrogen atom (where both X and Y do not represent -CH = at the same time), Z represents an oxygen atom or a sulfur atom, and T represents a sulfur atom. , Carbon atom or nitrogen atom, ring A represents a 5-7 member monocycle, ring B represents a 5-7 member monocycle or an 8-10 member bicycle, L ¹ represents a bond, − O -, - CONH -, - CO -, - CO 2 -, - S -, - SO 2 - or an -SO-, ^{L 2} is a bond, C1 -3 alkylene group, C3-7 cycloalkylene group Alternatively, it represents a phenylene group, where R ¹ is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, N (R ^1a ) ₂ (where, the two R ^1a are independent hydrogen atoms or C1 to 4 alkyl groups, respectively. ), C1-4 alkyl group, carboxy group, C1-4 alkoxycarbonyl group, C1-4 haloalkyl group, methyl-d ₃ group, C3-7 cycloalkyl group, phenyl group or 3-7 member monocyclic group Representing a non-aromatic heterocycle, R ^2c represents a hydrogen atom, a hydroxyl group, a halogen atom, an oxo group, a nitro group, a cyano group, a C1 to 4 alkoxy group or −CH ₂ NR ^2d R ^2e or NR ^2d R ^2e (here). , R ^2d represents a hydrogen atom, C1-4 alkyl group or R ^FR , R ^2e represents a hydrogen atom), m represents an integer of 0 or 1, and R ³ represents a hydrogen atom, a halogen atom. , Hydroxyl group, C1-4 alkyl group, C1-4 alkoxy group, C1-4 haloalkyl group, C1-4 haloalkoxy group or amino group, n represents an integer of 1 to 16 (where n is 2 or more). cases, groups represented by a plurality of ^{R 3} may be the same or ^{different.), R 4a} is a hydrogen atom, C1 -4 alkyl group, a carboxy group, or ^{R FR, R 5} is C1 -4 alkyl group the stands, p is (here, when p is 2 or more, groups represented by a plurality of ^{R 5} may be the same or different.) represents an integer of 0 to ^{5, R 6a} is a hydrogen atom, C1 to 4 Alkoxy group or R ^FR , R ⁷ represents a hydrogen atom, b represents the bond position of ring B, and R ^FR is − (CR ^Fb ₂ ) _q OP (= O) (OR ^Fa ) ₂ [Equation Among them, R ^Fa independently represents a hydrogen atom, a C1 to 4 alkyl group, a C3 to 6 cycloalkyl group, − (CH ₂ ) ₂ OH or −CH ₂ OCO ₂ CH (CH ₃ ) ₂ , and R ^Fb represents a hydrogen atom or a methyl group, and q is an integer of 1 or 2. (Here, the groups represented by the plurality of ^RFbs may be the same or different. ). ] Is represented. However, two or more of R ^2d , R ^4a and R ^6a do not represent R ^FR at the same time. ], A pharmaceutically acceptable salt thereof or a solvate thereof. Ring A is a 5-6 member monocyclic heterocycle containing (a) C5-6 monocyclic carbocycles or (b) 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur atoms. A compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof. Ring B is a 5-6 member monocyclic heterocycle containing (a) C5-6 monocyclic carbocycles or (b) 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur atoms. A compound according to claim 1 or 2, a pharmaceutically acceptable salt thereof, or a solvate thereof. Claim A is a 5- to 6-membered monocyclic aromatic heterocycle containing (a) a benzene ring or (b) 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur atoms. The compound according to 1 or 3, a pharmaceutically acceptable salt thereof, or a solvate thereof. Claim B is a 5- to 6-membered monocyclic aromatic heterocycle containing (a) a benzene ring or (b) 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur atoms. The compound according to any one of 1, 2 and 4, a pharmaceutically acceptable salt thereof, or a solvate thereof. The invention according to any one of claims 1, 3 and 5, wherein the ring A represents a 5- to 6-membered monocyclic aromatic nitrogen-containing heterocycle containing 1 to 4 nitrogen atoms and no other heteroatoms. Compounds, their pharmaceutically acceptable salts or solvates thereof. The compound according to any one of claims 1 to 6, wherein Z is an oxygen atom, a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound according to any one of claims 1 to 7, wherein X is a nitrogen atom and Y is −CH =, a pharmaceutically acceptable salt thereof, or a solvate thereof. Of the general formula (I-1)

[In the formula, the arrow is bonded to the carbon atom represented by b in the general formula (I-1), and the other symbols have the same meaning as in claim 1. ] Is the formula (Ib-1)

[In the formula, U represents a nitrogen atom or a carbon atom (where m represents 0 when U represents a nitrogen atom and m represents 1 when U represents a carbon atom), W represents − CR ³ = or represents a nitrogen atom, V represents -CH = or a nitrogen atom, and if the formula (Ib-1) has more than one R ³ , the groups they represent may be the same or different, and others. The symbols have the same meanings as described above and claim 1. ], Which is the group according to any one of claims 1 to 8, a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound represented by the general formula (I-1) is the general formula (II-1).

[In the formula, all symbols have the same meaning as claims 1 and 9. ], Which is the compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound according to any one of claims 1 to 10, wherein T is a nitrogen atom, a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound according to any one of claims 9 to 11, wherein U is a carbon atom, a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound according to any one of claims 1, 3, 5 and 7 to 12, wherein the ring A is pyrazole, triazole, tetrazole, oxazole, isooxazole, imidazole, thiazole or isothiazole, which is pharmaceutically acceptable. Salts or their solvates. The compound represented by the general formula (I-1) is the general formula (III-1).

[In the formula, pa represents an integer of 0 to 2, and other symbols have the same meaning as claims 1 and 9. ], Which is the compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound according to any one of claims 1 to 14, wherein L ² is a bond or a C1 to 3 alkylene group, a pharmaceutically acceptable salt thereof, or a solvate thereof. L ¹ is, -CONH-, (provided that the left of the group is attached to the ring _{B.) - CO -, -} CO 2 -, - S -, - SO 2 - or -SO-, claim 1 The compound according to any one of 1 to 15, a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound according to any one of claims 1 to 16, wherein R ¹ is a hydrogen atom or a C1 to 4 alkyl group, a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound according to any one of claims 1 to 17, wherein R ^2c is a nitro group or NR ^2d R ^2e , a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound according to any one of claims 1 to 18, wherein R ³ is a hydrogen atom, a halogen atom or a hydroxyl group, a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound according to any one of claims 1 to 19, wherein R ^4a is a hydrogen atom or R ^FR , and R ^2d and R ^6a are both hydrogen atoms, a pharmaceutically acceptable salt thereof, or a solvate thereof. Stuff. -(CR ^Fb ₂ ) _q OP (= O) (OR ^Fa ) ₂ represented by R ^FR is -CH ₂ OP (= O) (OH) ₂ , -CH (CH ₃ ) OP (= O) (OH) ₂ or -CH ₂ OP (= O) (OH) (OCH ₂ OCO ₂ CH (CH ₃ ) ₂ ) The compound according to any one of claims 1 to 20, a pharmaceutically acceptable salt thereof or Those solvates. The compound according to any one of claims 1 to 21, wherein p and pa are zero or one, a pharmaceutically acceptable salt thereof, or a solvate thereof. The compound represented by the general formula (I-1) is
(1) 4- (4-Amino-2-fluoro-5-methoxyphenyl) -7- (1H-pyrazole-4-yl) isoxazolo [5,4-c] pyridine-3-amine,
(2) 4- (4-Amino-2-fluoro-5-methoxyphenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridine-3-amine,
(3) 4- (4-Amino-3-methoxyphenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridine-3-amine,
(4) 4- (4-Amino-2-fluoro-5- (methylthio) phenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine,
(5) 4- (4-Amino-2-fluoro-5- (methoxy-d ₃ ) phenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine,
(6) 4- (4-Amino-2-fluoro-5- (methylsulfonyl) phenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine,
(7) 4- (4-Amino-5- (ethylthio) -2-fluorophenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine,
(8) 4- (4-Amino-2-fluoro-5- (methylsulfinyl) phenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine,
(9) 4- (4-Amino-2-fluoro-3-methoxyphenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridine-3-amine,
(10) Methyl 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorobenzoate,
(11) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorobenzoic acid,
(12) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorobenzamide,
(13) 4- (4-Amino-2-fluoro-5-methoxyphenyl) -7- (3-methyl-1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine,
(14) Methyl 2-amino-5- (3-amino-7- (1-((phosphonooxy) methyl) -1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl)- 4-Fluorobenzoate,
(15) 1- (2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorophenyl) ethane- 1-on,
(16) 4- (4-Amino-2-chloro-5- (methylthio) phenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine,
(17) Ethyl 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorobenzoate,
(18) (4- (4- (5-Acetyl-4-amino-2-fluorophenyl) -3-aminoisoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazole-1- Il) Methyl dihydrogen phosphate,
(19) Ethyl 2-amino-5- (3-amino-7- (1-((phosphonooxy) methyl) -1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl)- 4-Fluorobenzoate,
(20) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluoro-N-methylbenzamide,
(21) 1- (2-Amino-5- (3-Amino-7- (1H-Pyrazole-4-yl) isoxazolo [4,5-c] Pyridine-4-yl) -4-fluorophenyl) Propane- 1-on,
(22) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -N-ethyl-4-fluorobenzamide,
(23) 1- (2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) phenyl) ethane-1-one,
(24) Methyl 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) benzoate,
(25) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -N-propylbenzamide,
(26) 1- (2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorophenyl) butane- 1-on,
(27) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluoro-N-propylbenzamide,
(28) 1- (2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) phenyl) butane-1-one,
(29) 2-Hydroxyethyl 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-fluorobenzoate,
(30) 2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) benzamide,
(31) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -N-methylbenzamide,
(32) (4- (3-Amino-4- (4-amino-5- (ethylcarbamoyl) -2-fluorophenyl) isoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazole-1 -Il) Methyl dihydrogen phosphate,
(33) 1- (2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-hydroxyphenyl) ethane- 1-on,
(34) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -N-ethylbenzamide,
(35) 1- (2-amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) phenyl) propan-1-one,
(36) 2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl) -4-chloro-N-ethylbenzamide,
(37) (4- (3-Amino-4- (4-amino-2-fluoro-5- (methylthio) phenyl) isoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazole-1- Il) Methyl dihydrogen phosphate,
(38) (4- (3-Amino-4- (4-amino-2-fluoro-5-propionylphenyl) isoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazol-1-yl) Methyl dihydrogen phosphate,
(39) (4- (4- (3-Acetyl-4-aminophenyl) -3-aminoisoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazole-1-yl) methyldi Hydrogen phosphate,
(40) 4- (2-Fluoro-5-methoxy-4-nitrophenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-3-amine,
(41) (4- (3-Amino-4- (4-amino-2-fluoro-5- (methylsulfonyl) phenyl) isoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazole-1 -Il) Methyl dihydrogen phosphate,
(42) (4- (3-Amino-4- (4-amino-5- (ethylcarbamoyl) -2-chlorophenyl) isoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazole-1- Il) Methyl dihydrogen phosphate,
(43) 1- (2-Amino-5- (3-amino-7- (1H-pyrazole-4-yl) isothiazolo [4,5-c] pyridin-4-yl) -4-fluorophenyl) ethane- 1-one and (44) 4- (4-amino-2-fluoro-5- (trifluoromethyl) phenyl) -7- (1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridine- The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvate thereof, which is a compound selected from the group consisting of 3-amines. The compound represented by the general formula (I-1) is
(1) Methyl 2-amino-5- (3-amino-7- (1-((phosphonooxy) methyl) -1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl)- 4-Fluorobenzoate,
(2) (4- (4- (5-Acetyl-4-amino-2-fluorophenyl) -3-aminoisoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazole-1- Il) Methyl dihydrogen phosphate,
(3) Ethyl 2-amino-5- (3-amino-7- (1-((phosphonooxy) methyl) -1H-pyrazole-4-yl) isoxazolo [4,5-c] pyridin-4-yl)- 4-Fluorobenzoate,
(4) (4- (3-Amino-4- (4-amino-5- (ethylcarbamoyl) -2-fluorophenyl) isoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazole-1 -Il) Methyl dihydrogen phosphate,
(5) (4- (3-Amino-4- (4-amino-2-fluoro-5- (methylthio) phenyl) isoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazole-1- Il) Methyl dihydrogen phosphate,
(6) (4- (3-Amino-4- (4-amino-2-fluoro-5-propionylphenyl) isoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazol-1-yl) Methyl dihydrogen phosphate,
(7) (4- (4- (3-Acetyl-4-aminophenyl) -3-aminoisoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazole-1-yl) methyldi Hydrogen phosphate,
(8) (4- (3-Amino-4- (4-amino-2-fluoro-5- (methylsulfonyl) phenyl) isoxazolo [4,5-c] pyridin-7-yl) -1H-pyrazole-1 -Il) Methyl dihydrogen phosphate, and (9) (4- (3-amino-4- (4-amino-5- (ethylcarbamoyl) -2-chlorophenyl) isoxazolo [4,5-c] pyridin-7- The compound according to claim 1, a pharmaceutically acceptable salt thereof, or a solvent product thereof, which is a compound selected from the group consisting of -1H-pyrazole-1-yl) methyl dihydrogen phosphate. A pharmaceutically acceptable salt of the compound according to any one of claims 1 to 24, wherein the pharmaceutically acceptable salt of the compound according to any one of claims 1 to 24 is an alkali metal salt. The solvate. The compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof as a solvate is a hydrate. Solvation of salts allowed in. A pharmaceutical composition containing a compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. An agent for suppressing the progression of cancer or an infectious disease, suppressing recurrence, and / or treating a compound represented by the general formula (I-1) or a pharmaceutically acceptable salt thereof as an active ingredient. 28. The agent of claim 28, wherein the cancer is solid cancer or blood cancer. Solid cancers include malignant melanoma, non-small cell lung cancer, small cell lung cancer, head and neck cancer, renal cell cancer, breast cancer, ovarian cancer, clear ovarian adenocarcinoma, nasopharyngeal cancer, uterine cancer, anal cancer, colon cancer, Rectal cancer, colon cancer, hepatocellular carcinoma, esophageal cancer, gastric cancer, esophagogastric junction cancer, pancreatic cancer, urinary tract epithelial cancer, prostate cancer, oviduct cancer, primary peritoneal cancer, malignant pleural mesoderma, bile sac cancer Cancer, biliary tract cancer, skin cancer, testicular cancer (embryonic cell tumor), vaginal cancer, genital cancer, penis cancer, small bowel cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal cancer, spinal tumor, neuroblastoma 29. The agent of claim 29, which is one or more cancers selected from, medullary blastoma, ocular retinal blastoma, neuroendocrine tumor, brain tumor and squamous cell carcinoma. The agent according to claim 29, wherein the solid cancer is bone / soft tissue sarcoma or Kaposi's sarcoma. 29. The agent of claim 29, wherein the hematological malignancies are one or more cancers selected from multiple myeloma, malignant lymphoma, leukemia, primary malignant lymphoma of the central nervous system, myelodysplastic syndrome and myeloproliferative syndrome. The agent according to any one of claims 28 to 32, which is further administered in combination with one or more other anticancer agents. The agent according to claim 33, wherein the other anticancer agent is a cancer immunotherapeutic agent. The agent according to claim 34, wherein the cancer immunotherapeutic agent is an anti-PD-1 antibody or an anti-PD-L1 antibody. A STING agonist containing a compound represented by the general formula (I-1), a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.

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